naosite: nagasaki university's academic output siteefficient and selective formation of...

This document is downloaded at: 2017-12-22T10:24:31Z

Title Studies on Regio- and Stereoselective Multicomponent Coupling Reactionvia Nickelacycles

Author(s) Mori, Takamichi

Citation Nagasaki University (長崎大学), 博士(工学) (2014-11-19)

Issue Date 2014-11-19

URL http://hdl.handle.net/10069/34931

Right

NAOSITE: Nagasaki University's Academic Output SITE

http://naosite.lb.nagasaki-u.ac.jp

Studies on Regio- and Stereoselective Multicomponent Coupling Reaction via Nickelacycles

ニッケラサイクルを介した位置および立体選択的多成分連結反応に関する研究

September 2014 2014年 9月

Graduate School of Engineering Nagasaki University

長崎大学大学院工学研究科

Takamichi Mori 森崇理

Contents

Preface 1

General Introduction 3

Chapter 1 13

Multicomponent Coupling Reaction via Oxanickelacycle:

Stereoselective Coupling Reaction of Dimethylzinc and Alkyne

toward Nickelacycles

Chapter 2 57

Multicomponent Coupling Reaction via Azanickelacycle:

Ni-Catalyzed Homoallylation of Polyhydroxy N,O-Acetals with

Conjugated Dienes Promoted by Triethylborane

Chapter 3

Multicomponent Coupling Reaction via Nickelacycle: 109

Efficient and Selective Formation of Unsaturated Carboxylic Acids

and Phenylacetic Acids from Diketene

Publication List 165

1

Preface

The studies presented in this thesis have been carried out under the direction of Professor

Dr. Masanari Kimura at the Graduate School of Engineering, Nagasaki University during April

2009 to September 2014. This thesis is concerned with the development of Highly Regio-

and Stereoselective Multi-Component Coupling Reaction via Nickelacycles. The author has

been a Research Fellow of the Japan Society for the Promotion of Science during April 2012 to

March 2015.

The author would like to express his grateful gratitude to Professor Dr. Masanari Kimura

for his kind guidance, valuable suggestions, and continuous encouragement throughout this

work.

He is sincerely grateful to Associate Professor Shyuji Tanaka, Associate Professor

Yasuhiro Arikawa and Dr. Gen Onodera for his pertinent guidance and helpful discussions.

He is also grateful to Ms. Mariko Togawa (up to March 2010) and Mr. Toshiyuki Nakamura

(up to March 2013) for their valuable comments and discussions.

Furthermore, he wishes to thank Mr. Yushichiro Ohama, NMR Facility, for his helpful

suggestions and splendid assistance throughout this study, Ms. Junko Nagaoka for their

assistance with X-ray crystallographic analysis, and Mr. Noriaki Yamaguchi and Mr. Nobuaki

Tsuda of Joint Research Division for their measurements of mass spectra and elemental

analysis. He is also grateful to all of his colleagues and members of Professor Kimura’s

research group for his encouragement and helpful discussions.

Support from Research Fellowships of the Japan Society for the Promotion of Science for

Young Scientists is gratefully acknowledged.

Finally, the author thanks his family, Mr. Kingo Mori, Ms. Miyuki Mori, Ms. Sayaka

Mori, Ms. Saori Mori, Mr. Taisuke Mori, and Ms. Yoko Sakimoto for their constant

encouragement and affectionate assistance.

September 2014

Takamichi Mori

3

General Introduction

Synthetic organic chemistry creates ways important organic compounds, such as

physiologically active substances and functionalized molecules. Carbon–carbon

bond formation is the most meaningful strategy in synthetic organic chemistry.

Catalytic reactions using transition metals, such as Suzuki-Miyaura cross

coupling reaction1 and Negishi cross coupling reaction2, are the most powerful tools

for the efficient and selective carbon–carbon bond formations. Transition-metal

catalyzed organic reactions have been developed for the efficient synthesis of useful

compounds in many practical ways3.

Especially, nickelacycles and heteronickelacycles made from unsaturated

hydrocarbons and Ni-complex are attractive and convenient intermediates for C–C

bond formation (Scheme 1)4.

Scheme 1

Metalacycles are well-known as a important active intermediate for synthetic

organic chemistry5. However, oxametalacycles, in which carbon atom replaced by

the oxygen atom, have not been used as active intermediates.

Recently, it became clear that oxanickelacycle could be used as a very useful

R

R Ni

R

R

R

NiO

R

R NiN

R' R'

R''

Nickelacycle Oxanickelacycle Azanickelacycle

R

Ni

R

R

R

R NiO

R'R

R NiN

R'

R''

R

R

4

active intermediate for the catalytic reactions. In 1997, Montgomery and

co-workers have found a reductive coupling reaction of alkyne and aldehyde via

oxanickelacycle to provide allylalcohols 1 (eq. 1)6. Kimura, Tamaru and

co-workers have reported that the reductive coupling reaction of conjugated diene

and aldehyde via oxanickelacycle to provide bishomoallylalcohols 2 in 1998 (eq. 2)7.

Furthermore, Kimura and Tamaru developed multicomponent coupling reaction of

unsaturated hydrocarbon and carbonyl compounds via oxanickelacycle as active

intermediates8. The first example of the isolation oxanickelacycle has been reported

by Ogoshi and Kurosawa in 2004 (eq. 3, Figure 1)9. Since then, many reports on

the catalytic reaction via oxanickelacycles have been appeared. And the related

organic synthesis have been developed to construct complicated molecules.

cat. Ni(0) n-Bu3P Et2Zn

THF

NiO R2

L L

+R2

R1 H R3

O

R1R3

R3

OH

R2

H

R1

(1)

1

R2

R1

+

cat. Ni(0)Et3B

THF R3

OH

R1

R2

H R3

O R3

R2 H

ONi

L L

R1 (2)

2

NiONi

O

PCy3

Cy3PH O

toluene(3)

3

+ Ni(cod)2 + PCy3

5

Figure 1. ORTEP Drawing of Oxanickelacycle 3

This thesis is composed of three chapters.

Chapter 1: Multicomponent coupling reaction of alkyne, Me2Zn and vinylic cyclic

compounds via oxanickelacycle is described.

Chapter 2: Multicomponent coupling reaction of alkyne, Et3B and N,O-acetals

prepared from cyclic hemiacetals and primary amines via azanickelacycle is

developed.

Chapter 3: Selective formation of unsaturated carboxylic acid and phenyl acetic acid

from diketene via nickelacycles as active intermediates is demonstrated.

Chapter 1 deals with Ni-catalyzed three-component coupling reaction of alkynes,

Me2Zn, and vinyloxacyclopropane or vinylcyclopropane through oxanickelacycle

intermediates to provide dienyl homoallylalcohols and α-dienyl malonates (Scheme 2)10.

The reaction is readily conducted by exposing of Me2Zn to a mixture of

vinyloxacyclopropane and alkynes at room temperature under nitrogen atmosphere.

Alkynes tends to attack on the terminal carbon atom of the vinylic group to afford

heptadienyl alcohols with mixture of E and Z isomers. Furthermore, the coupling

6

reactions of alkynes, Me2Zn, and vinylcyclopropane derived from dimethyl malonate

and 1,4-dichloro-2-butene under similar catalytic conditions are also investigated. The

reaction proceeds smoothly at room temperature within several hours and the coupling

products are obtained with excellent E-stereoselectivities.

Scheme 2

Chapter 2 descibes that Ni-catalyzed homoallylation of N,O-acetals prepared from

cyclic hemiacetals and primary amines to provide ω-hydroxybishomoallylamines in

high regio- and stereoselectivity (Scheme 3)11. In similar catalytic reaction systems,

N,O-acetals from carbohydrates with primary amines give rise to the polyhydroxy-

bishomoallylamines as physiologically active molecules for development of medicinal

and synthetic chemistry.

O+

R1

R2

cat. Ni(0)+ Me2Zn R2

Me

R1

OH

+R1

R2


Me

R1E EE = CO2Me E selective

E, Z mixture

E

E

R+

cat. Ni(0)

Et3B+R1NH2

OHO

R2 R HN R1

OHR2n n

R+

cat. Ni(0)

Et3B+R1NH2

RR3

HN R1

OHO

O

OH

HO R3

R3

7

Scheme 3

Chapter 3 deals with selective formation of unsaturated carboxylic acids and

phenyl acetic acids from diketene (Scheme 4). It’s shown that Ni-catalyzed

multicomponent coupling reaction of alkyne, dimethylzinc, and diketene (as butenoic

acid equivalent) to provide 3-methylene-4-hexenoic acids in a single manipulation

(path A)12. On the other hand, in the presence of Ni catalyst, a formal [2+2+2]

cycloaddition reaction with diketene and two equivalents of alkynes proceeds to give

phenylacetic acid derivatives by use of Et2Al(OEt) instead of Me2Zn (path B).

Furthermore, in the presence of Ni catalyst and PPh3 under the similar catalytic

conditions, the regioselectivity was changed dramatically to provide the symmetrical

substituted phenylacetic acid as a single product via C–C double bond cleavage of

diketene (path C, D).

Ni-catalyzed oxidative cyclization of alkyne and diketene seems to form

nickelacyclopentene intermediate. In the absence of phosphine ligand, the ring

expansion reaction undergoes to form oxanickelacycle intermediate, whereas, in the

presence of phosphine ligand, the active nickelacycle bearing PPh3 ligand invokes C–

C bond cleavage reaction via nickel carbene cyclopropane rearrangement13.

Scheme 4

+

R1

R2

cat. Ni(0)

Me2Zn(path A)

R1 •OH

O•Me

R2

cat. Ni(0)

Et2Al(OEt)(path B)

•

•

OH

O

R1

R2

R1

R2

!

••

OO

!

+

R1

R2

cat. Ni/PPh3

Me2Al(OMe)(path D)

R1 •OH

OMe•

R2

cat. Ni/PPh3

Et2Al(OEt)(path C)

•

•OH

O

R1

R2

••

OO

!

R2

R1

8

References

(1) (a) Miyaura, N.; Suzuki, A. J. Chem. Soc., Chem. Commun. 1979, 866.

(b) Miyaura, N.; Yamada, K.; Suzuki, A. Tetrahedron Lett. 1979, 3437.

(c) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11, 513.

(2) (a) Baba, S.; Negishi, E. J. Am. Chem. Soc. 1976, 98, 6729.

(b) Negishi, E.; Baba, S. J. Chem. Soc., Chem. Commun. 1976, 596.

(c) King, A. O.; Okukado, N.; Negishi, E. J. Chem. Soc., Chem. Commun. 1977,

683.

(d) Negishi, E.; King, A. O.; Okukado, N. J. Org. Chem. 1977, 42, 1821.

(e) Negishi, E.; Van Horn, D. E. J. Am. Chem. Soc. 1977, 99, 3168.

(f) King, A. O.; Negishi, E.; Villani, F. J., Jr.; Silveira, A., Jr. J. Org. Chem. 1978,

43, 358.

(3) Reviews: (a) J. Montgomery, Acc. Chem. Res. 2000, 33, 467.

Reviews: (b) S.-i. Ikeda, Acc. Chem. Res. 2000, 35, 511.

Reviews: (c) S. Saito; Y. Yamamoto, Chem. Rev. 2000, 100, 2901.

Reviews: (d) I. Nakamura; Y. Yamamoto, Chem. Rev. 2004, 104, 2127.

(e) J. Montgomery, Angew. Chem. Int. Ed. 2004, 43, 3890-3908; Angew. Chem.

2004, 116, 3980.

(f) Y. Tamaru, Modern Organonickel Chemistry; Wiley-VCH: Weinheim, 2005.

9

(g) R. M. Moslin; K. M. Moslin; T. F. Jamison, Chem. Commun. 2007, 4441.

(h) F.-S. Han, Chem. Soc. Rev. 2013, 42, 5270.

(4) (a) Tasker, Z. S.; Standley, A. E.; Jamison, F. T. Nature, 2014, 509, 299.

(b) Yamasaki, R.; Ohashi, M.; Maeda, K.; Kitamura, T.; Nakagawa, M.; Kato, K.;

Fujita, T.; Kamura, R.; Kinoshita, K.; Masu, H.; Azumaya, I.; Ogoshi, S.; Saito, S.

Chem. Eur. J. 2013, 19, 3415.

(c) Nishimura, A; Ohashi, M.; Ogoshi, S. J. Am. Chem. Soc. 2012, 134, 15692.

(d) Jenkins, D. A.; Herath, A.; Song, M.; Montgomery, J. J. Am. Chem. Soc. 2011,

133, 14460.

(e) Tombe, R.; Kurahashi, T.; Matsubara, S. Org. Lett., 2013, 15, 1791.

(f) Nakao, Y.; Morita, E.; Idei, H.; Hayama, T. J. Am. Chem. Soc. 2011, 133,

3264.

(5) (a) 中村晃, 安田源, 有機合成化学協会誌, 1980, 38, 975.

(b) 山崎博史, 岩槻康雄, 化学総説「有機金属錯体の化学」, 日本化学会,

1981, No. 32, 161.

(6) Oblinger, E.; Montgomery, J. J. Am. Chem. Soc. 1997, 119, 9065.

(7) Kimura, M.; Ezoe, A.; Shibata, K.; Tamaru, Y. J. Am. Chem. Soc. 1998, 120,

4033.

10

(8) (b)Kimura, M.; Ezoe, A.; Tanaka, S.; Tamaru, Y. Angew. Chem. Int. Ed. 2001,

40, 3600.

(c) Kimura, M.; Ezoe, A.; Mori, M.; Iwata, K.; Tamaru, Y. J. Am. Chem. Soc.

2006, 128, 8559.

(d) Tamaru, Y.; Kimura, M. Organic Syntheses 2006, 83, 88.

(e) Kimura, M.; Fujimatsu, H.; Ezoe, A.; Shibata, K.; Shimizu, M.; Matsumoto,

S.; Tamaru, Y. Angew. Chem. Int. Ed. 1999, 38, 397.

(f) Kimura, M.; Miyachi, A.; Kojima, K.; Tanaka, S.; Tamaru, Y. J. Am. Chem.

Soc. 2004, 126, 14360.

(g) Kimura, M.; Ezoe, A.; Mori, M.; Tamaru, Y. J. Am. Chem. Soc. 2005, 127,

201.

(h) Kojima, K.; Kimura, M.; Tamaru, Y. Chem. Commun. 2005, 4717.

(i) Kimura, M.; Kojima, K.; Tatsuyama, Y.; M.; Tamaru, Y. J. Am. Chem. Soc.

2006, 128, 6332.

(j) Kimura, M.; Mori, M.; Mukai, R.; Kojima, K.; Tamaru, Y. Chem. Commun.

2006, 3813.

(k) Kojima, K.; Kimura, M.; Ueda, S.; Tamaru, Y. Tetrahedron 2006, 62, 7512.

(l) Ikeda, S.-i.; Cui, D.-M.; Sato, Y. J. Org. Chem. 1994, 59, 6877.

(m) Ikeda, S.-i.; Miyashita, H.; Sato, Y. Organometallics 1998, 17, 4316.

(n) Cui, D.-M.; Tsuzuki, T.; Miyake, K.; Ikeda, S.-i.; Sato, Y. Tetrahedron 1998,

54, 1063.

11

(9) Ogoshi, S.; Oka, M.; Kurosawa, H. J. Am. Chem. Soc. 2004, 126, 11802.

(10) (a) Mori, T.; Nakamura, T.; Kimura, M. Org. Lett., 2011, 13, 2266.

Highlighted in Synfacts, 7, pp.0767-0767 (2011).

(b) Mori, T.; Nakamura, T.; Onodera, G.; Kimura, M. Synthesis, 2012, 44, 2333.

(11) Mori, T.; Akioka, Y.; Onodera, G.; Kimura, M. Molecules, 2014, 17, 9288.

(12) Mori, T.; Akioka, Y.; Kawahara, H.; Ninokata, R.; Onodera, G.; Kimura, M.

Angew. Chem. Int. Ed., accepted for publication (ASAP).

(13) Palladacyclopentene rearrangements involving Pd carbene complex have been

reported by B. M. Trost et al :

(a) B. M. Trost, G. J. Tanoury, J. Am. Chem. Soc. 1988, 110, 1636.

(b) B. M. Trost, M. Yanai, K. Hoogsteen, J. Am. Chem. Soc. 1993, 115, 5294.

(c) B. M. Trost, A. S. K. Hashmi, J. Am. Chem. Soc. 1994, 116, 2183.

13

Chapter 1

Multicomponent Coupling Reaction via Oxanickelacycle:

Stereoselective Coupling Reaction of Dimethylzinc and Alkyne toward

Nickelacycles

Summary: Ni-catalyzed three-component coupling reaction of Me2Zn, alkynes, and

vinyloxacyclopropanes and vinylcyclopropanes to afford dienyl alcohols and α-hep-

tadieneyl dimethyl malonates in excellent yields with high stereoselectivities.

O+

R1

R2


Me

R1

OH

+R1

R2


Me

R1E EE = CO2Me E selective

E, Z mixture

E

E

14

Introduction

Multicomponent coupling reaction is among the most efficient and

straightforward synthetic strategies for C–C bond transformation1. Especially,

Ni-catalyzed coupling reactions, which have involving unsaturated hydrocarbons, are

widely utilized for the synthesis of physiologically active compounds and complicated

molecules2. We previously reported the Ni(0) catalyst accelerated oxidative

cyclization of aldehydes and conjugated dienes in the presence of Et3B3 and Et2Zn4, with

subsequent reductive coupling, to provide bis-homoallyl alcohols with excellent regio-

and stereoselectivities through key oxanickelacycle intermediates. Furthermore, we

demonstrated that similar catalytic systems promoted the four-component coupling of

1,3-butadiene, alkynes, aldehydes, and dimethylzinc to provide 3,6-octadienyl alcohols

with excellent regio- and stereoselectivities (Scheme 1)5.

Ikeda et al. repored the Ni-catalyzed three-component coupling reaction of allyl

chloride, an alkyne, and Me2Zn in the presence of Ni catalyst via the syn stereoselective

addition manner of π-allylnickel species followed by methyl group transfer to the

alkyne carbon atom to construct 1,4-pentadiene skeletons (Scheme 2)6.

15

Scheme 1. Multicomponent Coupling of Diene, Alkyne, Carbonyls, and Me2Zn

Scheme 2. Ni-Catalyzed Coupling of Allylhalides, Alkyne, and Me2Zn

Furthermore, the Ni(0) metal-catalyzed coupling reaction of alkyne-tethered

vinylcyclopropanes with allyl chloride has been reported7. In this case, the addition of

the π-allylnickel species to the alkyne moiety proceeds with β-syn elimination of the

cyclopropyl C–C bond giving the (E)-1,3-diene with excellent regio- and

+R1

R1

Ni-catalyst

Me2Zn+ R2CHO

R2Me

R1OH

R2

+R1

R1

Ni-catalyst

Me2Zn+ R2CHO

R2Me

R1NHR3

R2

+ R3NH2

+H

R

cat.NiCl2(PPh3)2

Me2ZnR

Me

H

X

16

stereoselectivities. Encouraged by these multicomponent coupling reactions involving

π-allylnickel species by Ikeda’s protocols and our previous strategies utilizing

oxanickelacycles with alkynes and organozinc reagents, we were prompted to develop

stereodefined functionalizations using allylating agents and alkynes based on the

structural variety of oxanickelacycles.

Herein, we would like to report highly regio- and stereocontrolled three-

component coupling reaction of alkynes, dimethylzinc, and vinyloxacyclopropane,

vinylcyclopropanes involving the addition of π-allylnickel species toward the alkynes to

provide 2,5-heptadienyl alcohols and 2,5-heptadienyl malonates.

17

Results and Discussion

The reaction was readily conducted by exposing Me2Zn to a mixture of

vinyloxacyclopropane and alkynes at room temperature under nitrogen atmosphere.

The results using various kinds of ligands and solvents are shown in Table 1. The

initial investigation using vinyloxacyclopropane and 3-hexyne made it clear that THF

was the most effective solvent (entries 1-8, Table 1). In all cases, the alkynes tended

to attack on the terminal carbon atom of the vinylic group to afford heptadienyl alcohol

3aa via methyl group transfer from Me2Zn in a 3:1 ratio of E and Z isomers with respect

to the C-2 olefin geometry. Among these results with various kinds of ligands using

monodentate, bidentate phosphine ligands, and NHC ligands, no ligands at room

temperature provided the best result in the formation of the desired product (entries 9-13,

Table 1).

Next, we conducted the multicomponent coupling reaction of substituted

vinyloxacyclopropane, various alkynes, and Me2Zn under the optimized conditions of

Table 1. Although diphenylacetylene participated in the coupling reaction in good

yield to afford a mixture of E and Z isomers (entry 1, Table 2), bis(trimethylsilyl)acety-

lene and an electron-deficient alkyne did not provide the desired results (entries 2 and 3,

Table 2). An unsymmetrical alkyne took part in the coupling reaction in excellent

yields to give 3ae as four inseparable regio- and stereoisomers and 3af as two

stereoisomers (entries 4 and 5, Table 2).

18

Table 1. Optimization of Reaction Conditions for the Nickel-Catalyzed Three-Component Coupling Reaction of Alkyne, Vinyloxacyclopropane and Me2Zna

entry ligand solvent condition yield of 3aa (%) [E/Z]

1 none THF r.t., 24 h 92 [3:1]

2b none THF r.t., 24 h 90 [3:1]

3 none THF 50 ˚C, 24 h 89 [3:1]

4 none toluene 80 ˚C, 24 h 81 [3:1]

5 none toluene 110 ˚C, 24 h 82 [3:1]

6 none ether r.t., 24 h 84 [3:1]

7 none CH2Cl2 r.t., 24 h 59 [3:1]

8 none dioxane r.t., 24 h 20 [3:1]

9 Ph3P THF r.t., 48 h 71 [3:1]

10 n-Bu3P THF r.t., 48 h no reaction

11c dppf THF r.t., 48 h no reaction

12d dppbz THF r.t., 48 h 59 [3:1]

O+

Et

Et

cat. Ni(acac)2+ Me2Zn

Et

Me

Et

OH1a 2a

3aa

19

(Table 1, continued)

13e NHC THF r.t., 24 h 81 [1:1]

a The reaction was conducted in the presence of vinyloxacyclopropane (1 mmol), Ni(acac)2 (0.1 mmol), ligand (0.2 mmol), 3-hexyne (1 mmol), and dimethylzinc (1.2 mmol; 1 M hexane) in solvent (3 mL) under nitrogen atmosphere. b Ni(cod)2 (0.1 mmol) was used instead of Ni(acac)2. c dppf: diphenylphosphinoferrocene (0.1 mmol) was used. d dppbz: diphenylphosphinobenzene (0.1 mmol) was used. e NHC ligand was prepared from 1,3-bis(2,6-diisopropylphenyl)- imidazolium chloride with 0.2 mmol of t-BuOK.

Two equivalents of terminal alkynes were required to afford the products 3ag and

3ah in modest yields along with the branched regioisomers 4ag and 4ah, which were

produced by attack of the terminal alkynes on the internal allylic position of

vinyloxacyclopropane (entries 6 and 7, Table 2). 2-Methyl-2-vinyloxacyclopropane

underwent a similar coupling reaction in good to excellent yields, and employment of

3-hexyne and diphenylacetylene led to the formation of the desired product 3ba and

3bb in high yields in a 1:2 to 1:3 ratios of E and Z stereoisomers (entries 8 and 9, Table

2). Bis(trimethylsilyl)acetylene showed the modest yield and selectivity as well as the

result of butadiene monoxide (entry 10, Table 2).

20

Table 2. Scope of the Nickel-Catalyzed Three-Component Coupling Reaction

of Vinyloxacyclopropane 1 with Alkyne 2a

entry epoxide R alkyne R1 R2 yield of 3 and 4 (%) [E/Z]

1 H (1a) Ph Ph (2b) 3ab: 84 [2:1]

2 H (1a) TMS TMS (2c) 3ac: 35 [2:1]

3 H (1a) CO2Me CO2Me (2d) no reaction

4 H (1a) Et Ph (2e) 3ae: 93 [4 isomers]

5 H (1a) Me TMS (2f) 3af: 97 [2:1]

6b H (1a) H Ph (2g) 3ag: 81 [2:1], 4ag: 15

7b H (1a) H TMS (2h) 3ah: 64 [2:1], 4ah: 33

8 Me (1b) Et Et (2a) 3ba: >99 [1:2]

9 Me (1b) Ph Ph (2b) 3bb: 73 [1:3]

10 Me (1b) TMS TMS (2c) 3bc: 61 [1:1]

a The reaction was undertaken in the presence of vinyloxacyclopropane (1 mmol), Ni(acac)2 (0.1 mmol), alkyne (1 mmol), and dimethylzinc (1.2 mmol; 1 M hexane) in THF (3 mL) under nitrogen atmosphere. b Alkyne (4 mmol) was used.

O+

R1

R2

cat. Ni(acac)2

r.t., 24 h+ Me2Zn

R2

Me

R1

OH

1 2

3

R

R

R1

Me

R2 OH

4

+

21

Based on the optimized catalytic systems, we examined the multicomponent

coupling reaction of vinyloxacyclopropane and substituted alkynes, and dimethylzinc in

the multi-grams scale to give the corresponding dienyl alcohols 3 and 4 in good to

reasonable yields. In that case, even if it reduces catalyst quantity to 1 mol%, it is

satisfactory (Table 3).


of Vinyloxacyclopropane 1 with Alkyne 2 on a 15-mmol Scalea

entry epoxide R alkyne R1 R2 yield of 3 and 4 (%) [E/Z]

1 H (1a) Et Et (2a) 3aa: 99 [3:1]

2 H (1a) Ph Ph (2b) 3ab: 99 [2:1]

3 H (1a) TMS TMS (2c) 3ac: 41 [2:1]

4 H (1a) Et Ph (2e) 3ae: 95 [4 isomers]

5 H (1a) Me TMS (2f) 3af: 97 [2:1]

O+

R1

R2

cat. Ni(acac)2

r.t., 24 h+ Me2Zn

R2

Me

R1

OH

1 2

3

R

R

R1

Me

R2 OH

4

+

22


6b H (1a) H Ph (2g) 3ag: 37 [2:1], 4ag: 18

7b H (1a) H TMS (2h) 3ah: 27 [2:1], 4ah: 10

8 Me (1b) Et Et (2a) 3ba: 93 [1:2]

9 Me (1b) Ph Ph (2b) 3bb: 84 [1:3]

10 Me (1b) TMS TMS (2c) 3bc: 41 [1:1]

a The reaction was undertaken in the presence of vinyloxacyclopropane (18 mmol), Ni(acac)2 (0.15 mmol), alkyne (15 mmol), and dimethylzinc (15 mmol; 1 M hexane) in THF (30 mL) under nitrogen atmosphere. b Alkyne (45 mmol) was used.

23

A plausible reaction mechanism for the multicomponent coupling reaction of

vinyloxacyclopropane, alkyne, and dimethylzinc is displayed in Scheme 3. Low

stereoselectivities for the coupling reactions using vinyloxacyclopropane might

originate from the formation of the π-allyloxanickelacycle intermediate I in equilibrium

with the 6-membered oxanickelacycle II. It is known that vinyloxacyclopropane

readily undergoes oxidative addition toward Ni(0) metal species coordinated by alkynes

to form four- or six-membered oxanickelacycles. This is followed by methyl group

transfer from the Zn atom to the Ni metal center, leading to C–C bond formation and a

mixture of E and Z isomers. Terminal carbons of phenylacetylene and trimethylsilyla-

cetylene attack on the allylic position of vinyloxacyclopropane to afford the branched

regiosomers 4 owing to less steric repulsion between the H atom of the terminal alkyne

and the allylic moiety of intermediate III (Scheme 3).

24

Scheme 3. Reaction Mechanism for Three-Component Coupling Reaction of

Vinyloxacyclopropane, Alkyne and Me2Zn

Ni O

R2

R1ONi

R2

R1

R2 OZnMe

R1

NiMe

ZnMe2 ZnMe2

R2

R1

NiMeOZnMe

OR1 R2

Ni(0)+ + Me2Zn

R1 < R2

R2 OH

R1

Me

R2

R1

MeOH

(E)-3 (Z)-3

- Ni(0)- Ni(0)

I II

Ni O

R2

H

ZnMe2R2

NiMeOZnMe - Ni(0) R2

MeOH

In case of R1 = H

III 4

25

The coupling reaction with various alkynes, dimethylzinc, and vinylcyclopropane,

which is prepared from dimethyl malonate with 1,4-dichloro-2-butene, are summarized

in Table 4. In most cases, the reaction proceeded smoothly at room temperature within

several hours and the coupling products were obtained with excellent E-stereoselectiv-

ities (entries 1 and 2, Table 4). The trimethylsilyl group also took part in efficient

coupling to give the corresponding desired product 5cc in moderate yield with E-stereo-

selectivity (entry 3, Table 4). And an electron-deficient alkyne did not provide the

desired result (entry 4, Table 4). Unsymmetrical internal alkynes participated in the

coupling reaction giving rise to a mixture of regioisomers with exclusive E-stereosele-

ctivities (entries 5 and 6, Table 4). In all cases, the stereochemistry with respect to the

Me group and the olefinic main chain is the Z-form, as in the reaction of vinylcyclopro-

pane. The reaction feature using terminal alkyne such as phenylacetylene and trimet-

hylsilylacetylene were changed dramatically and the desired product 5 was not obtained

at all. Instead, the dienynes 7cg and 7ch, involving dimerization of the terminal

alkynes, were produced as major products by the stereoselective coupling reaction with

vinylcyclopropane (entries 7 and 8, Table 4).

26


of Vinylcyclopropane 1c with Alkyne 2a

entry alkyne R1 R2 time (h) yield of 5, 6 and 7 (%) [E/Z]

1 Et Et (2a) 1 5ca: 84 [E only]

2 Ph Ph (2b) 3 5cb: 73 [E only]

3 TMS TMS (2c) 3 5cc: 63 [E only]

4 CO2Me CO2Me (2d) 24 no reaction

5 Et Ph (2e) 6 5ce: 92 [E only]b

6 Me TMS (2f) 1 5cf: 83 [E only]

7c H Ph (2g) 24 7cg: 71 [E only]

8c H TMS (2h) 6 7ch: 56 [E only], 6ch: 24

a The reaction was undertaken in the presence of vinylcyclopropane (1 mmol), Ni(acac)2 (0.1 mmol), alkyne (1 mmol), and dimethylzinc (1.2 mmol; 1 M hexane) in THF (3 mL) under nitrogen atmosphere. b Product 5ce was obtained as a mixture of regioisomer in a 3:1 ratio. c Alkyne (4 mmol) was used.

+R1

R2

cat. Ni(acac)2

r.t., time (h)+ Me2Zn

R2

Me

R1

1c 2

5R1

Me

R2

6

+

E EE = CO2Me

E

E

E

E

R2+ E

E

7

R2

27

Moreover, Also in a multi-gram scale, a reaction advances equal, and this reaction

gives the same products. In that case, even if it reduces catalyst quantity to 1 mol%, it is

satisfactory (Table 5).


of Vinylcyclopropane 1c with Alkyne 2 on a 15-mmol Scalea

entry alkyne R1 R2 time (h) yield of 5, 6 and 7 (%) [E/Z]

1 Et Et (2a) 24 5ca: 80 [E only]

2 Ph Ph (2b) 24 5cb: 68 [E only]

3 TMS TMS (2c) 24 5cc: 59 [E only]

4 Et Ph (2e) 24 5ce: 83 [E only]b

5 Me TMS (2f) 24 5cf: 91 [E only]

6c H Ph (2g) 24 7cg: 65 [E only]

a The reaction was undertaken in the presence of vinylcyclopropane (1 mmol), Ni(acac)2 (0.1 mmol), alkyne (1 mmol), and dimethylzinc (1.2 mmol; 1 M hexane) in THF (3 mL) under nitrogen atmosphere. b Product 5ce was obtained as a mixture of regioisomer in a 3:1 ratio. c Alkyne (4 mmol) was used.

+R1

R2

cat. Ni(acac)2

r.t., 24 h+ Me2Zn

R2

Me

R1

1c 2

5R1

Me

R2

6

+

E EE = CO2Me

E

E

E

E

R2+ E

E

7

R2

28

The stereochemistry of the products was unequivocally determined on the basis of

NOE experiments. The results of irradiation at the bold protons are illustrated in

Figure 1. According to the NOE results, irrespective of the kinds of regioisomers

derived from the symmetrical and unsymmetrical alkynes, it was apparent that methyl

group transfer from Me2Zn to the acetylenic triple bond proceeded in a syn manner to

deliver Z-stereochemistry with respect to the C5 olefinic geometry and E-stereo-

chemistry with respect to the C2 position by the ring expanding reaction processes of

the vinylcyclopr- opyl groups.

Figure 1. NOE Data for the Irradiation at the Bold Methylene Protons.

Me3Si

E

EMe

Me H H

Ph

E

E

Me H H E

EPh

Me H H

8.0%

11.3%

6.3% 12.3%

9.2%5cf: E = CO2Me

5ce (major isomer) 5ce (minor isomer)

29

A reaction mechanism for the coupling reaction of alkyne, vinylcyclopropane, and

Me2Zn is displayed in Scheme 4. The exclusive E-stereochemistry might stem from

the stability of the produced nickelacycles. Formation of allylnickel species IV would

predominate over that of 8-membered ring species V owing to the entropy effect for the

ring-closing reaction. This is followed by insertion of the alkyne to the allylic termi-

nus of the allylnickel species to provide (E)-5 isomer exclusively. As in the case of

using terminal alkyne, zinc acetylide derived from dimethylzinc and terminal alkyne

might preferentially participate in the coupling reaction via transmetalation with allyl-

nickel species VI to give rise to diene-yne 7 as the major products. Since Ni(0)

catalysts tend to promote a head-to-tail dimerization of terminal alkynes in the presence

of organozinc reagents to give the enyne framework, the aleternative coupling reaction

involving dimerization of terminal alkyne followed by carbonickelation toward vinyl-

cyclopropane to provide diene-yne 7 might be probable8.

30

Scheme 4. Reaction Mechanism for Three-Component Coupling Reaction of

Vinylcyclopropane, Alkyne and Me2Zn

R2

R1

Ni

R2

R1

R2

R1

NiMe

ZnMe2 ZnMe2

R2

R1

NiMe

R1 R2Ni(0)

+ + Me2Zn

R1 < R2

(E)-5 (Z)-5

- Ni(0)- Ni(0)

IV V

- Ni(0)

In case of R1 = H

E EE = CO2Me

O

E

OMeNi

OOMe

E

EOMe

OZnMe

EOMe

OZnMe

R2

R1

Me

R2

R1

MeE

EE

E

VI

Ni

R2

H

ZnMe2

O

E

OMe ZnMe

R2

(E)-7

R2 E

E

R2

31

In summary, we have demonstrated Ni-catalyzed multicomponent coupling

reaction of vinyloxacyclopropane, alkyne, and dimethylzinc to provide 2,5-heptadienyl

alcohols as a mixture of E and Z isomers in high yields. Furthermore, vinylcyclopro-

pane participated in highly regio- and stereoselective multicomponent coupling reac-

tion to afford dimethyl(α-2,5-heptadienyl)malonates with excellent E-stereoselectivity.

And we have succeeded to extend these reactions in multi-grams scale for the efficient

synthesis of dienyl alcohols and sterodefined dienyl esters9. These reactions could be

performed with standard laboratories glassware and equipment and did no require the

expensive and specialized chemicals and catalysts.

32

Experimental Section

Reactions employed oven-dried glassware unless otherwise noted. Thin layer

chromatography (TLC) employed glass 0.25 mm silica gel plates with UV indicator

(Merck, Silica gel 60F254

). Flash chromatography columns were packed with 230-400

mesh silica gel as a slurry in hexane. Gradient flash chromatography was conducted

eluting with a continuous gradient from hexane to the indicated solvent. Distillation

were carried out in a Kugelrohr apparatus (SIBATA glass tube oven GTO-350RG).

Boiling points are meant to refer to the oven temperature (± 1 °C). Microanalyses

were performed by the Instrumental Analysis Center of Nagasaki University. Analysis

agreed with the calculated values within ± 0.4%. Proton and carbon NMR data were

obtained with a JEOL-GX400 with tetramethylsilane as an internal standard.

Chemical shift values were given in ppm downfield from the internal standard.

Infrared spectra were recorded with a JASCO A-100 FT-IR or SHIMAZU FTIR-8700

spectrophotometer. High resolution mass spectra (HRMS) were measured with a

JEOL JMS-DX303.

Solvents and Reagents

Tetrahydrofuran, diethyl ether, and 1,4-dioxane were dried and distilled from

benzophenone and sodium immediately prior to use under nitrogen atmosphere.

Anhydrous toluene and dichloromethane were purchased (Aldrich) and used without

further purification. Ni(acac)2, PPh3, n-Bu3P, dppf [1,1’-bis(diphenylphosphino)ferro-

33

cene], 1,3-bis(2,6-di-isopropylphenyl)imidazolium chloride, and Me2Zn (1.0 M hexane

solution) (Kanto Kagaku) were purchased and used without further purification.

3-Hexyne, dimethylacetylene, bis(methoxycarbonyl)ethyne, 1-phenyl-1-butyne, phenyl-

acetylene, trimethylsilylacetylene, bistrimethylacetylene, and diphenylacetylene (Tokyo

Kasei Kogyo Co., Ltd) were purchased and distilled prior to use. Butadiene monoxide

and isoprene oxide (Aldrich) were purchased and distilled prior to use. Dimethyl

2-vinylcyclopropane-1,1-dicarboxylate was prepared according to the literature10.

34

General procedure 1: for the Nickel-catalyzed three-component coupling reaction

of alkynes, vinyloxacyclopropane and Me2Zn (entry 1, Table 1)

An oven-dried, 25 mL, three-necked round-bottomed flask equipped with a dropp-

ing funnel, a rubber septum cap, an air condenser (fitted with a three-way stopcock

connected into nitrogen balloon), and a Teflon-coated magnetic stir bar was charged

with Ni(acac)2 (25.7 mg, 0.1 mmol). The apparatus was purged with nitrogen and the

flask was charged successively via syringe with freshly dry THF (3 mL), vinyloxacy-

clopropane (70.1 mg, 1 mmol), and 3-hexyne (82.1 mg, 1 mmol). Dimethylzinc (1.2

mmol, 1.0 M hexane solution) was added slowly at room temperature via the dropping

funnel over a period of 10 min (the reaction temperature should not be exceeded 50 ˚C).

The mixture was stirred at room temperature for 24 h and monitored by TLC. After

the reaction was completed, the reaction mixture was cooled to 0 ˚C, and then poured

into ice-water. The resulting solution was diluted with 30 mL of EtOAc and carefully

washed with 2 M HCl, with sat. NaHCO3, and brine. The aqueous layer was extracted

with 30 mL of EtOAc. The combined organic phases were dried (MgSO4) and conce-

ntrated in vacuo, and the residual oil was subjected to column chromatography over

silica gel (eluent; hexane/EtOAc = 16/1 v/v) to afford 3aa as a colorless oil (155.6 mg,

92%; Rf = 0.45; hexane/EtOAc = 4/1 v/v); bp 100 ˚C /0.1 mmHg.

35

(2E,5E)-5-Ethyl-6-methylocta-2,5-dien-1-ol : (3aa)

(2E,5E)-5-Ethyl-6-methylocta-2,5-dien-1-ol (3aa): (a mixture of E- and Z- isomers in

a ratio of 3 : 1): IR (neat) 3319 (m), 2962 (s), 2931 (s), 2872 (s), 1655 (w), 1458 (m),

1373 (m), 1070 (m), 1004 (m), 970 (m), 792 (w) cm-1; 1H NMR (400 MHz, CDCl3,

(E)-) δ 0.94 (t, J = 7.6 Hz, 3 H), 0.97 (t, J = 7.6 Hz, 3 H), 1.62 (s, 3 H), 2.03 (q, J = 7.6

Hz, 2 H), 2.04 (q, J = 7.6 Hz, 2 H), 2.75 (br m, 2 H), 4.09 (br m, 2 H), 5.62 (m, 2 H);

13C NMR (100 MHz, CDCl3, (E)-) δ 13.3, 13.6, 17.5, 24.9, 27.0, 34.7, 63.8, 127.9,

128.8, 131.2, 131.6; 1H-NMR (400 MHz, CDCl3, (Z)-): δ 0.94 (t, J = 7.6 Hz, 3 H), 0.97

(t, J = 7.6 Hz, 3 H), 1.58 (s, 3 H), 2.03 (q, J = 7.6 Hz, 2 H), 2.04 (q, J = 7.6 Hz, 2 H),

2.80 (d, J = 7.3 Hz, 2 H), 4.26 (br m, 2 H), 5.45 (dt, J = 11.0, 7.3 Hz, 1 H), 5.58 (dm, J

= 11.0 Hz, 1 H); 13C-NMR (100 MHz, CDCl3, (Z)-) δ 13.2, 13.6, 17.5, 24.8, 27.1, 30.2,

58.7, 127.9, 128.8, 131.0, 131.4; High-resolution MS, calcd for C11H20O: 168.1514.

Found m/z (relative intensity): 169(M++1, 1), 168.1497 (M+, 8), 167 (20), 151 (27),

150 (31), 139 (100).

(2E,5Z)-5,6-Diphenylhepta-2,5-dien-1-ol : (3ab)

Following General Procedure 1. Purification by flash chromatography (eluent; hexane/

EtOAc = 8/1 v/v) afforded 3ab as a colorless oil. bp 180 °C/0.1 mmHg.

EtOH

Et

36

(2E,5Z)-5,6-Diphenylhepta-2,5-dien-1-ol (3ab): (a mixture of E- and Z- isomers in a

ratio of 2 : 1): IR (neat) 3350 (s), 3055 (s), 3020 (s), 2993 (s), 2928 (s), 2870 (m), 1717

(s), 1682 (s), 1599 (m), 1489 (s), 1443 (s), 1026 (m), 970 (m), 912 (m), 764 (m) cm-1;

1H NMR (400 MHz, CDCl3, (E)-) δ 2.17 (s, 3 H), 3.31 (br m, 2 H), 4.10 (br m, 2 H),

5.72 (m, 2 H), 7.00 (m, 10 H); 13C NMR (100 MHz, CDCl3, (E)-) δ 21.1, 37.9, 63.6,

125.6, 127.4, 127.5, 128.9, 129.0, 129.4, 129.5, 129.6, 134.7, 142.8, 143.1, 144.1; 1H

NMR (400 MHz, CDCl3, (Z)-): δ 2.20 (s, 3 H), 3.34 (d, J = 6.6 Hz, 2 H), 4.00 (d, J =

6.3 Hz, 2 H), 5.57 (dt, J = 10.2, 6.6 Hz, 1 H), 5.72 (dt, J = 10.2, 6.3 Hz, 1 H), 7.00 (m,

10 H); 13C NMR (100 MHz, CDCl3, (Z)-) δ 20.9, 33.5, 58.4, 125.8, 127.4, 127.5, 128.9,

129.3, 129.4, 129.5, 129.6, 135.4, 142.8, 143.1, 144.0; High-resolution MS, calcd for

C19H20O: 264.1514. Found m/z (relative intensity): 264.1440 (M+, 42), 263 (100), 262

(51), 246 (57).

(2E,5Z)-5,6-Bis(trimethylsilyl)hepta-2,5-dien-1-ol : (3ac)

Following General Procedure 1. Purification by flash chromatography (eluent;

hexane/EtOAc = 12/1 v/v) afforded 3ac as a colorless oil. bp 110 °C/0.1 mmHg.

(2E,5Z)-5,6-Bis(trimethylsilyl)hepta-2,5-dien-1-ol (3ac): (a mixture of E- and Z-

PhOH

Ph

TMSOH

TMS

37

isomers in a ratio of 2 : 1): IR (neat) 3329 (m), 2955 (s), 2899 (m), 2864 (m), 1456 (w),

1248 (s), 1001 (m), 968 (m), 837 (s), 756 (m) cm-1; 1H NMR (400 MHz, CDCl3) δ 0.12

(s, 18 H), 1.26 (br, 1 H), 1.78 (s, 3 H), 2.89 (d, J = 7.6 Hz, 2 H), 4.26 (d, J = 6.3 Hz, 2

H), 5.60-5.68 (m, 2 H); 13C NMR (100 MHz, CDCl3, (E)-) δ 0.4, 17.6, 33.4, 63.8,

128.6, 130.3, 142.9; 13C NMR (100 MHz, CDCl3, (Z)-) δ 0.4, 17.6, 31.6, 60.3, 128.6,

130.3, 143.3; High-resolution MS, calcd for C13H28OSi2: 256.1679. Found m/z (relative

intensity): 257 (M++1, 24), 256.1679 (M+, 100), 225 (9).

(2E,5E)-5-Ethyl-6-phenylhepta-2,5-dien-1-ol : (3ae)

Following General Procedure 1. Purification by flash chromatography (eluent;

hexane/EtOAc = 8/1 v/v) afforded 3ae as a colorless oil. bp 150 °C/0.1 mmHg.

(2E,5E)-5-Ethyl-6-phenylhepta-2,5-dien-1-ol (3ae): (a mixture of 4 isomers, the ratio

was not determined): IR (neat) 3350 (s), 3057 (m), 3020 (m), 2968 (s), 2933 (s), 2873

(s), 1717 (s), 1682 (s), 1599 (m), 1491 (s), 1441 (s), 1026 (s), 972 (m), 766 (s) cm-1; 1H

NMR (400 MHz, CDCl3, (2E)-) δ 0.89 (t, J = 7.6 Hz, 3 H), 1.58 (br s, 1 H), 1.89 (q, J

= 7.6 Hz, 2 H), 1.93 (s, 3 H), 2.94 (br m, 2 H), 4.14 (br m, 2 H), 5.73 (m, 2 H), 7.10 (t,

J = 7.6 Hz, 2 H), 7.21 (d, J = 7.6 Hz, 2 H), 7.30 (t, J = 7.6 Hz, 1 H); 13C NMR (100

MHz, CDCl3, (2E)-) δ 13.4, 21.0, 26.2, 33.8, 63.7, 125.8, 127.8, 127.9, 128.5, 129.3,

130.4, 130.9, 144.9; 1H NMR (400 MHz, CDCl3, (2Z)-) δ 0.90 (t, J = 7.6 Hz, 3 H),

PhOH

Et

38

1.31 (br s, 1 H), 1.89 (q, J = 7.6 Hz, 2 H), 1.95 (s, 3 H), 2.98 (d, J = 7.3 Hz, 2 H), 4.31

(d, J = 6.6 Hz, 2 H), 5.56 (dt, J = 10.7, 7.3 Hz, 1 H), 5.67 (dt, J = 10.7, 6.6 Hz, 1 H),

7.10 (t, J = 7.6 Hz, 2 H), 7.21 (d, J = 7.6 Hz, 2 H), 7.29 (t, J = 7.6 Hz, 1 H); 13C NMR

(100 MHz, CDCl3, (2Z)-) δ 13.3, 20.9, 26.1, 29.4, 58.7, 125.8, 127.9, 127.9, 128.6,

129.2, 130.4, 130.9, 144.9; High-resolution MS, calcd for C15H20O: 216.1514. Found

m/z (relative intensity): 217 (M++1, 16), 216.1496 (M+, 100), 214 (15), 199 (36).

(2E,5E)-5-methyl-6-(trimethylsilyl)hepta-2,5-dien-1-ol: (3af)

Following General Procedure 1, Purification by distillation afforded 3af as a color less

oil. bp 115 °C/0.1mmHg.

(2E,5E)-5-methyl-6-(trimethylsilyl)hepta-2,5-dien-1-ol (3af): (a mixture of 2E- and

2Z- isomers in a ratio of 2 : 1): IR (neat): 3312 (s), 2953 (s), 2912 (s), 2860 (m), 1612

(m), 1445 (m), 1247 (s), 1001 (m), 835 (s), 756 (s), 687 (m) cm-1; 1H NMR (400 MHz,

CDCl3, (E)- ): δ 0.12 (s, 9 H), 1.26 (brs, 1 H), 1.70 (s, 3 H), 1.78 (s, 3 H), 2.84 (d, J =

7.4 Hz, 2 H), 4.09 (d, J = 6.3 Hz, 2 H), 5.45-5.65 (m, 2 H); 13C NMR (100 MHz,

CDCl3, (E)-): δ 0.4, 17.6, 21.1, 37.9, 63.7, 128.4, 129.2, 131.9, 142.9; 1H NMR (400

MHz, CDCl3, (Z)- ): δ 0.13 (s, 9 H), 1.35 (brs, 1 H), 1.71 (s, 3 H), 1.85 (s, 3 H), 2.89 (d,

J = 7.4 Hz, 2 H), 4.25 (d, J = 6.3 Hz, 2 H), 5.45-5.65 (m, 2 H); 13C NMR (100 MHz,

CDCl3, (Z)-): δ 0.7, 17,6, 22.9, 34.3, 58.6, 128.6, 129.8, 130.3, 144.7; High-resolution

MS, calcd for C11H22OSi: 198.1440. Found m/z (relative intensity): 199 (M++1, 10),

TMS

Me

Me

OH

39

198.1431 (M+, 60), 183 (20) 169 (16) 127 (100).


of alkynes, vinyloxacyclopropane and Me2Zn (entry 6, Table 1)





flask was charged successively via syringe with freshly dry THF (3 mL), vinyloxacy-

clopropane (70.1 mg, 1 mmol), and phenylacetylene (409 mg, 4 mmol). Dimethylzinc

(1.2 mmol, 1.0 M hexane solution) was added slowly at room temperature via the

dropping funnel over a period of 10 min (the reaction temperature should not be

exceeded 50 ˚C). The mixture was stirred at room temperature for 24 h and monitored

by TLC. After the reaction was completed, the reaction mixture was cooled to 0 ˚C,

and then poured into ice-water. The resulting solution was diluted with 30 mL of

EtOAc and carefully washed with 2 M HCl, with sat. NaHCO3, and brine. The

aqueous layer was extracted with 30 mL of EtOAc. The combined organic phases

were dried (MgSO4) and concentrated in vacuo, and the residual oil was subjected to

column chromatography over silica gel (eluent; hexane/EtOAc = 16/1 v/v) to afford 3ag

as a colorless oil (152.4 mg, 81%; Rf = 0.40; hexane/EtOAc = 4/1 v/v).

(2E,5E)-6-Phenylhepta-2,5-dien-1-ol : (3ag)

40

(2E,5E)-6-Phenylhepta-2,5-dien-1-ol (3ag): (a mixture of E- and Z- isomers in a ratio

of 2 : 1): IR (neat) 3371 (br), 3024 (s), 2926 (s), 2872 (s), 1719 (m), 1647 (m), 1495 (s),

1447 (s), 1028 (s), 927 (s), 760 (s), 698 (s) cm-1; 1H NMR (400 MHz, CDCl3, (E)-): δ

1.55 (br, 1 H), 2.05 (t, J = 1.0 Hz, 3 H), 2.99 (t, J = 7.0 Hz, 2 H), 4.12 (d, J = 5.3 Hz, 1

H), 4.27 (d, J = 5.3 Hz, 1 H), 5.60-5.80 (m, 3 H), 7.21 (tt, J = 7.0, 2.0 Hz, 1 H), 7.30

(td, J = 7.0, 1.5 Hz, 2 H), 7.36 (dt, J = 7.0, 1.3 Hz, 2 H); 13C NMR (100 MHz, CDCl3,

(E)-) δ 15.8, 31.4, 63.6, 125.5, 126.6, 128.0, 128.2, 129.4, 130.7, 135.9, 143.5; 1H

NMR (400 MHz, CDCl3, (Z)-): δ 1.55 (br, 1 H), 2.05 (t, J = 1.0 Hz, 3 H), 2.95 (t J =

7.0 Hz, 2 H), 4.12 (d, J = 5.3 Hz, 1 H), 4.27 (d, J = 5.3 Hz, 1 H), 5.60-5.80 (m, 3 H),

7.21 (tt, J = 7.0, 2.0 Hz, 1 H), 7.30 (td, J = 7.0, 1.5 Hz, 2 H), 7.36 (dt, J = 7.0, 1.3 Hz, 2

H); 13C NMR (100 MHz, CDCl3, (Z)-) δ 15.8, 27.3, 58.6, 125.5, 126.6, 128.0, 128.2,



(E)-4-Phenyl-2-vinylpent-3-en-1-ol: (4ag)

Following General Procedure 2, Purification by flash column chromatography afforded

4ag as a color less oil.

OH

Ph

(E)-4-Phenyl-2-vinylpent-3-en-1-ol (4ag): IR (neat): 3362 (br), 3080 (s), 2928 (s),

2872 (s), 1726 (s), 1636 (m), 1597 (m), 1493 (m), 914 (m), 758 (s), 696 (s) cm-1; 1H

PhOH

41

NMR (400 MHz, CDCl3): δ 1.54 (s, 1 H), 2.09 (d, J = 1.5 Hz, 3 H), 3.38 (ddt, J = 10.3,

9.0, 7.4 Hz 1 H), 3.62 (d, J = 7.4 Hz, 2 H), 5.17 (dd, J = 7.6, 1.5 Hz, 1 H), 5.20 (dd, J =

17.3, 1.5 Hz, 1 H), 5.63 (dq, J = 9.0, 1.5 Hz, 1 H), 5.78 (ddd, J = 17.3, 10.3, 7.6 Hz, 1

H), 7.24 (tt, J = 7.9, 2.3 Hz, 1 H), 7.31 (td, J = 7.9, 1.5 Hz, 2 H), 7.39 (dt, J = 7.9, 1.3

Hz, 2 H); 13C NMR (100 MHz, CDCl3): δ 16.4, 46.3, 65.5, 116.5, 125.6, 125.9, 126.9,



(2E,5E)-6-(Trimethylsilyl)hepta-2,5-dien-1-ol: (3ah)


3ah as a color less oil.

TMSOH

(2E,5E)-6-(Trimethylsilyl)hepta-2,5-dien-1-ol (3ah): (a mixture of E- and Z- isomers

in a ratio of 2 : 1): IR (neat): 3317 (br), 3009 (s), 2955 (s), 2899 (s), 1614 (m), 1404

(m), 1248 (s), 1013 (s), 970 (s), 837 (s), 750 (s), 689 (s) cm-1; 1H NMR (400 MHz,

CDCl3, (E)-): δ 0.01 (s, 9 H), 1.28 (s, 1 H), 1.63 (d, J = 0.9 Hz, 3 H), 2.84 (t, J = 6.9

Hz, 2 H), 4.06 (d, J = 5.6 Hz, 2 H), 5.62 (m, 3 H); 13C NMR (100 MHz, CDCl3, (E)-):

δ -2.1, 14.4, 31.2, 63.7, 128.5, 129.1, 131.0, 135.9; 1H NMR (400 MHz, CDCl3, (Z)-):

0.01 (s, 9 H), 1.28 (s, 1 H), 1.65 (d, J = 0.9 Hz, 3 H), 2.81 (t, J = 6.9 Hz, 2 H), 4.19 (d,

J = 5.6 Hz, 2 H), 5.62 (m, 3 H); 13C NMR (100 MHz, CDCl3, (Z)-): δ -2.1, 14.4, 27.0,

58.6, 128.5, 129.1, 131.0, 135.9; High-resolution MS, calcd for C10H20OSi: 184.1283.

42

Found m/z (relative intensity): 185 (M++1, 16), 184.1261 (M+, 100), 170 (12), 169 (82),

166(34).

(E)-4-(Trimethylsilyl)-2-vinylpent-3-en-1-ol: (4ah)


4ah as a color less oil.

OH

TMS

Me

(E)-4-(Trimethylsilyl)-2-vinylpent-3-en-1-ol (4ah): IR (neat): 3313 (br), 3080 (m),

2955 (s), 2874 (m), 1618 (m), 1406 (m), 1248 (s), 1028 (s), 991 (m), 835 (s), 750 (s),

689 (m) cm-1; 1H NMR (400 MHz, CDCl3): δ 0.07 (s, 9 H), 1.43 (s, 1 H), 1.73 (d, J =

1.7 Hz, 3 H), 3.38 (tdd, J = 8.5, 7.8, 6.7 Hz, 1 H), 3.52 (d, J = 7.8 Hz, 2 H), 5.11 (dd, J

= 17.6, 1.7 Hz, 1 H), 5.12 (dd, J = 9.8, 1.7 Hz, 1 H), 5.53 (dq, J = 8.5, 1.7 Hz, 1 H),

5.72 (ddd, J = 17.6, 9.8, 6.7 Hz, 1 H); 13C NMR (100 MHz, CDCl3): δ 1.6, 15.4, 46.3,

65.6, 116.7, 136.5, 137.9, 140.9; High-resolution MS, calcd for C10H20OSi: 184.1283.

Found m/z (relative intensity): 185 (M++1, 16), 184.1261 (M+, 100), 170 (12), 169 (82),

166(34).

(2Z,5E)-5-Ethyl-2,6-dimethylocta-2,5-dien-1-ol: (3ba)

Following General Procedure 1, Purification by distillation afforded 3ba as a color less

oil. bp 105 ˚C /0.1mmHg.

43

EtEt

OH

(2Z,5E)-5-Ethyl-2,6-dimethylocta-2,5-dien-1-ol (3ba): (a mixture of E- and Z-

isomers in a ratio of 1 : 2): IR (neat): 3336 (m), 2964 (s), 2934 (s), 2872 (s), 1653 (m),

1456 (s), 1375 (s), 1005 (s), 951 (w), 785 (w) cm-1; 1H NMR (400 MHz, CDCl3, (Z)-):

δ 0.94 (t, J = 7.6 Hz, 3 H), 0.96 (t, J = 7.6 Hz, 3 H), 1.64 (s, 3 H), 1.80 (d, J = 1.2 Hz, 3

H), 1.99 (q, J = 7.6 Hz, 2 H), 2.02 (q, J = 7.6 Hz, 2 H), 2.77 (d, J = 7.1 Hz, 2 H), 4.19

(s, 2 H), 5.21 (tq, J = 7.1, 1.2 Hz, 1 H); 13C NMR (100 MHz, CDCl3, (Z)-): δ 13.2, 13.6,

17.5, 21.3, 24.6, 27.1, 30.2, 61.7, 127.2, 130.5, 132.2, 133.7; 1H NMR (400 MHz,

CDCl3, (E)-): δ 0.94 (t, J = 7.6 Hz, 3 H), 0.96 (t, J = 7.6 Hz, 3 H), 1.64 (s, 3 H), 1.72 (s,

3 H), 1.99 (q, J = 7.6 Hz, 2 H), 2.02 (q, J = 7.6 Hz, 2 H), 2.75 (d, J = 6.6 Hz, 2 H), 4.00

(s, 2 H), 5.31 (t, J = 6.6 Hz, 1 H); 13C NMR (100 MHz, CDCl3, (E)-): δ 13.2, 13.6, 13.8,

17.6, 24.9, 27.1, 30.4, 69.1, 125.4, 130.5, 132.3, 134.2; High-resolution MS, calcd for

C12H22O: 182.1671. Found m/z (relative intensity): 183 (M++1, 10), 182.1669 (M+, 69),

164 (100).

(2Z,5Z)-2-Methyl-5,6-diphenylhepta-2,5-dien-1-ol: (3bb)

Following General Procedure 1, Purification by distillation afforded 3bb as a color less


PhPh

OH

(2Z,5Z)-2-Methyl-5,6-diphenylhepta-2,5-dien-1-ol (3bb): (a mixture of E- and Z-

44

isomers in a ratio of 1 : 3): IR (neat): 3350 (s), 3057 (m), 3024 (s), 2968 (s), 2933 (s),

2876 (s), 1719 (s), 1701 (s), 1670 (m), 1599 (m), 1491 (s), 1437 (s), 1026 (m), 912 (m),

760 (m) cm-1; 1H NMR (400 MHz, CDCl3, (Z)-): δ 1.55 (br s, 1 H), 1.74 (d, J = 1.2 Hz,

3 H), 2.20 (s, 3 H), 3.30 (d, J = 7.6 Hz, 2 H), 3.91 (s, 2 H), 5.31 (tq, J = 7.6, 1.2 Hz, 1

H), 6.92 - 7.08 (m, 10 H); 13C NMR (100 MHz, CDCl3, (Z)-): δ 20.9, 21.3, 33.8, 61.5,

124.6, 125.7, 127.4, 127.5, 128.9, 129.6, 135.2, 136.0, 143.0, 144.1. 1H NMR (400

MHz, CDCl3, (E)-): δ 1.55 (br s, 1 H), 1.63 (s, 3 H), 2.18 (s, 3 H), 3.30 (d, J = 7.6 Hz,

2 H), 3.97 (s, 2 H), 5.41 (t, J = 7.6 Hz, 1 H), 6.92 - 7.08 (m, 10 H); 13C NMR (100

MHz, CDCl3, (E)-): δ 13.8, 21.1, 33.8, 68.8, 123.5, 125.5, 127.4, 127.5, 129.0, 129.4,


m/z (relative intensity): 279 (M++1, 17), 278.1658 (M+, 73), 260 (100).

(2Z,5Z)-2-methyl-5,6-bis(trimethylsilyl)hepta-2,5-dien-1-ol: (3bc)

Following General Procedure 1, Purification by distillation afforded 3bc as a color less


TMS

OH

TMS

(2Z,5Z)-2-methyl-5,6-bis(trimethylsilyl)hepta-2,5-dien-1-ol (3bc): (a mixture of E-

and Z- isomers in a ratio of 1 : 1): IR (neat): 3396 (br), 2955 (s), 2899 (s), 1717 (s),

1699 (s), 1437 (m), 1248 (s), 1047 (s), 1009 (s), 839 (s), 756 (s), 689 (m) cm-1; 1H

NMR (400 MHz, CDCl3, (Z)-): δ 0.14 (s, 9 H), 0.18 (s, 9 H), 1.72 (s, 3 H), 1.80 (brs, 1

H), 1.83 (s, 3 H), 2.85 (d, J = 6.7 Hz, 2 H), 4.19 (d, J = 4.2 Hz, 2 H), 5.04 (t, J = 6.7 Hz,

45

1 H); 13C NMR (100 MHz, CDCl3, (Z)-): δ 0.81, 1.46, 13.9, 18.7, 25.4, 69.1, 124.3,

133.4, 143.9, 149.8; 1H NMR (400 MHz, CDCl3, (E)-): δ 0.13 (s, 9 H), 0.17 (s, 9 H),

1.72 (s, 3 H), 1.80 (brs, 1 H), 1.83 (s, 3 H), 2.83 (d, J = 6.8 Hz, 2 H), 4.19 (d, J = 4.2

Hz, 2 H), 5.02 (t, J = 6.8 Hz, 1 H); 13C NMR (100 MHz, CDCl3, (E)-): δ 0.81, 1.93,


C14H30OSi2: 270.1835. Found m/z (relative intensity): 270.1812 (M+, 100), 269 (72),

254 (94).


of alkynes, vinylcyclopropane and Me2Zn (entry 1, Table 3)

An oven-dried, 25 mL, three-necked round-bottomed flask equipped with a

dropping funnel, a rubber septum cap, an air condenser (fitted with a three-way

stopcock connected into nitrogen balloon), and a Teflon-coated magnetic stir bar was

charged with Ni(acac)2 (25.7 mg, 0.1 mmol). The apparatus was purged with

nitrogen and the flask was charged successively via syringe with freshly dry THF (3

mL), vinylcyclopropane (184 mg, 1 mmol), and 3-hexyne (82.1 mg, 1 mmol).

Dimethylzinc (1.2 mmol, 1.0 M hexane solution) was added slowly at room

temperature via the dropping funnel over a period of 10 min (the reaction temperature

should not be exceeded 50 ˚C). The mixture was stirred at room temperature for 1 h

and monitored by TLC. After the reaction was completed, the reaction mixture was

cooled to 0 ˚C, and then poured into ice-water. The resulting solution was diluted

46

with 30 mL of EtOAc and carefully washed with 2 M HCl, with sat. NaHCO3, and

brine. The aqueous layer was extracted with 30 mL of EtOAc. The combined

organic phases were dried (MgSO4) and concentrated in vacuo, and the residual oil

was subjected to column chromatography over silica gel (eluent; hexane/EtOAc = 16/1

v/v) to afford 5ca as a colorless oil (236.6 mg, 84%; Rf = 0.60; hexane/EtOAc = 4/1

v/v). bp 130 ˚C /0.1mmHg.

Dimethyl-2-((2E,5E)-5-ethyl-6-methylocta-2,5-dienyl)malonate: (5ca)

EtEt

CO2Me

CO2Me

Dimethyl-2-((2E,5E)-5-ethyl-6-methylocta-2,5-dienyl)malonate (5ca): IR (neat):

2959 (s), 2882 (m), 1738 (s), 1655 (w), 1437 (s), 1340 (m), 1269 (m), 1161 (m), 974

(m), 698 (w) cm-1; 1H NMR (400 MHz, CDCl3, (E)-): δ 0.91 (t, J = 7.6 Hz, 3 H), 0.96

(t, J = 7.6 Hz, 3 H), 1.54 (s, 3 H), 1.97 (q, J = 7.6 Hz, 2 H), 2.02 (q, J = 7.6 Hz, 2 H),

2.58 (ddd, J = 7.8, 6.8, 1.2 Hz, 2 H), 2.67 (d, J = 6.1 Hz, 2 H), 3.40 (t, J = 7.8 Hz, 1 H),

3.71 (s, 6 H), 5.32 (dt, J = 15.1, 6.8 Hz, 1 H), 5.46 (dtt, J = 15.1, 6.1, 1.2 Hz, 1 H); 13C

NMR (100 MHz, CDCl3, (E)-): δ 13.3, 13.6, 17.5, 24.7, 27.0, 31.9, 35.0, 52.1, 52.3,

52.7, 124.9, 127.7, 131.1, 131.8, 169.2, 172.4; High-resolution MS, calcd for

C16H26O4: 282.1831. Found m/z (relative intensity): 282.1829 (M+, 100), 253 (64), 251

(25).

Dimethyl-2-((2E,5Z)-5,6-diphenylhepta-2,5-dienyl)malonate: (5cb)

47

Following General Procedure 3, Purification by distillation afforded 5cb as a color less

oil. bp 190 ˚C /0.1mmHg

PhPh

CO2Me

CO2Me

Dimethyl-2-((2E,5Z)-5,6-diphenylhepta-2,5-dienyl)malonate (5cb): IR (neat): 3078

(w), 3020 (s), 2999 (m), 2953 (s), 1732 (s), 1599 (w), 1491 (m), 1435 (s), 1339 (m),

1267 (m), 1232 (m), 1198 (m), 1155 (s), 972 (w), 764 (s), 700 (s) cm-1; 1H NMR (400

MHz, CDCl3): δ 2.13 (s, 3 H), 2.60 (ddd, J = 7.6, 6.8, 1.0 Hz, 2 H), 3.23 (d, J = 5.9 Hz,

2 H), 3.38 (t, J = 7.6 Hz, 1 H), 3.69 (s, 6 H), 5.46 (dt, J = 15.1, 6.8 Hz, 1 H), 5.58 (dtt, J

= 15.1, 5.9, 1.0 Hz, 1 H), 6.90-7.06 (m, 10 H); 13C NMR (100 MHz, CDCl3): δ 21.0,

31.9, 38.2, 52.0, 52.3, 52.4, 125.5, 125.6, 127.3, 127.4, 128.6, 128.9, 129.4, 134.5,

134.9, 138.9, 143.3, 144.2, 169.1; High-resolution MS, calcd for C24H26O4: 378.1831.

Found m/z (relative intensity): 379 (M++1, 27), 378.1835 (M+, 100), 360 (3).

Dimethyl-2-((2E,5Z)-5,6-bis(trimethylsilyl)hepta-2,5-dienyl)malonate: (5cc)

Following General Procedure 3, Purification by distillation afforded 5cc as a color less


TMS COOMe

COOMe

TMS

Dimethyl-2-((2E,5Z)-5,6-bis(trimethylsilyl)hepta-2,5-dienyl)malonate (5cc): IR

(neat): 2957 (s), 1736 (s), 1456 (m), 1437 (m), 1340 (m), 1248 (s), 1198 (s), 1155 (s),

972 (m), 839 (m) cm-1; 1H NMR (400MHz, CDCl3): δ 0.15 (s, 18 H), 1.76 (s, 3 H),

48

2.62 (d, J = 6.4 Hz, 2 H), 2.62 (t, J = 7.5 Hz, 2 H), 3.42 (t, J = 7.5 Hz, 1 H), 3.75 (s, 6

H), 5.64-5.46 (m, 2 H); 13C NMR (100MHz, CDCl3): δ -2.1, 22.8, 32.1, 52.3, 125.5,

130.1, 143.2, 150.5, 169.3; High-resolution MS, calcd for C18H34O4Si2: 370.1996.

Found m/z (relative intensity): 371 (M++1, 22), 370.2006 (M+, 78), 355 (100), 339 (6).

Dimethyl-2-((2E,5E)-5-ethyl-6-phenylhepta-2,5-dienyl)malonate: (5ce)

Following General Procedure 3, Purification by distillation afforded 5ce as a color less


Ph CO2Me

CO2Me

Et major Et CO2Me

CO2Me

Ph minor

Dimethyl-2-((2E,5E)-5-ethyl-6-phenylhepta-2,5-dienyl)malonate (5ce): (a mixture

of regioisomers in a ratio of 3 : 1): IR (neat): 3020 (m), 2959 (s), 2934 (s), 1738 (s),

1491 (m), 1437 (s), 1232 (s), 1153 (s), 1026 (m), 970 (m), 768 (s), 704 (s) cm-1; 1H

NMR (400 MHz, CDCl3, (major)-): δ 0.86 (t, J = 7.4 Hz, 3 H), 1.85 (q, J = 7.4 Hz, 2

H), 1.90 (s, 3 H), 2.63 (td, J = 7.3, 1.2 Hz, 2 H), 2.85 (d, J = 6.2 Hz, 2 H), 3.44 (t, J =

7.3 Hz, 1 H), 3.72 (s, 6 H), 5.46 (dtt, J = 15.4, 7.3, 1.5 Hz, 1 H), 5.57 (dtt, J = 15.4, 6.2,

1.5 Hz, 1 H), 7.09 (dd, J = 7.5, 1.4 Hz, 2 H), 7.19 (tt, J = 7.5, 1.4 Hz, 1 H), 7.29 (td, J

= 7.5, 1.4 Hz, 2 H); 13C NMR (100 MHz, CDCl3, (major)-): δ 13.4, 20.9, 26.1, 31.9,

34.1, 52.0, 52.3, 125.5, 125.7, 127.7, 127.9, 128.5, 131.2, 134.5, 145.0, 169.2; 1H

NMR (400 MHz, CDCl3, (minor)-): δ 0.90 (t, J = 7.4 Hz, 3 H), 1.75 (s, 3 H), 1.91 (q, J

= 7.4 Hz, 2 H), 2.55 (td, J = 7.3, 1.2 Hz, 2 H), 2.98 (d, J = 6.2 Hz, 2 H), 3.35 (t, J = 7.3

Hz, 1 H), 3.69 (s, 6 H), 5.32 (dtt, J = 15.4, 7.3, 1.5 Hz, 1 H), 5.45 (dtt, J = 15.4, 6.2,

49

1.5 Hz, 1 H), 7.03 (dd, J = 7.5, 1.4 Hz, 2 H), 7.19 (tt, J = 7.5, 1.4 Hz, 1 H), 7.27 (td, J

= 7.5, 1.4 Hz, 2 H); 13C NMR (100 MHz, CDCl3, (minor)-): δ 13.2, 17.0, 28.5, 31.8,

37.9, 52.0, 52.3, 125.4, 125.7, 127.9, 128.5, 130.7, 131.9, 134.4, 143.8, 169.2;

High-resolution MS, calcd for C20H26O4: 330.1831. Found m/z (relative intensity): 371

(M++1, 23), 330.1832 (M+, 100), 315 (2), 301 (4), 299 (4).

Dimethyl-2-((2E,5E)-5-methyl-6-(trimethylsilyl)hepta-2,5-dienyl)malonate: (5cf)

Following General Procedure 3, Purification by distillation afforded 5cf as a color less

oil. bp 120 ˚C/0.1mmHg.

TMSMe

CO2Me

CO2Me

Dimethyl-2-((2E,5E)-5-methyl-6-(trimethylsilyl)hepta-2,5-dienyl)malonate (5cf):

IR (neat): 2955 (s), 1740 (s), 1612 (w), 1437 (m), 1340 (w), 1248 (m), 1155 (m), 972

(w), 856 (m), 837 (m), 756 (w), 689 (w) cm-1; 1H NMR (400 MHz, CDCl3): δ 0.12 (s,

9 H), 1.62 (d, J = 1.2 Hz, 3 H), 1.74 (q, J = 1.2 Hz, 3 H), 2.58 (ddd, J = 1.2, 6.8, 7.6 Hz,

2 H), 2.76 (d, J = 6.3 Hz, 2 H), 3.41 (t, J = 7.6 Hz, 1 H), 3.71 (s, 6 H), 5.34 (dt, J =

15.1, 6.8 Hz, 1 H), 5.46 (dtt, J = 15.1, 6.3, 1.2 Hz, 1 H); 13C NMR (100 MHz, CDCl3):

δ 0.40, 17.4, 22.9, 26.8, 31.9, 38.1, 52.0, 52.3, 125.5, 127.6, 130.6, 143.2, 169.2;

High-resolution MS, calcd for C16H28O4Si: 312.1757. Found m/z (relative intensity):

313 (M++22), 312.1743 (M+, 100), 297 (81).

50


of alkynes, vinylcyclopropane and Me2Zn (entry 7, Table 3)




charged with Ni(acac)2 (25.7 mg, 0.1 mmol). The apparatus was purged with

nitrogen and the flask was charged successively via syringe with freshly dry THF (3

mL), vinylcyclopropane (184 mg, 1 mmol), and phenylacetylene (409 mg, 4 mmol).

Dimethylzinc (1.2 mmol, 1.0 M hexane solution) was added slowly at room

temperature via the dropping funnel over a period of 10 min (the reaction temperature

should not be exceeded 50 ˚C). The mixture was stirred at room temperature for 24 h

and monitored by TLC. After the reaction was completed, the reaction mixture was


with 30 mL of EtOAc and carefully washed with 2 M HCl, with sat. NaHCO3, and

brine. The aqueous layer was extracted with 30 mL of EtOAc. The combined

organic phases were dried (MgSO4) and concentrated in vacuo, and the residual oil

was subjected to column chromatography over silica gel (eluent; hexane/EtOAc = 16/1

v/v) to afford 7cg as a colorless oil (276.7 mg, 71%; Rf = 0.55; hexane/EtOAc = 4/1

v/v).

Dimethyl-2-[(2E,5Z)-6,8-diphenylocta-2,5-dien-7-ynyl]malonate: (7cg)

51

Ph CO2Me

CO2Me

Ph

Dimethyl-2-[(2E,5Z)-6,8-diphenylocta-2,5-dien-7-ynyl]malonate (7cg): IR (neat):

3028 (s), 2953 (s), 2843 (m), 1738 (s), 1597 (m), 1489 (s), 1435 (s), 1155 (s), 1028 (s),

970 (m), 914 (m), 758 (s), 692 (s) cm-1; 1H NMR (400MHz, CDCl3): δ 2.63 (td, J = 7.6,

1.0 Hz, 2 H), 3.25 (td, J = 6.9, 1.0 Hz, 2 H), 3.43 (t, J = 7.6 Hz, 1 H), 3.71 (s, 6 H),

5.53 (dtt, J = 15.4, 6.9, 1.3 Hz, 1 H), 5.65 (dtt, J = 15.4, 7.6, 1.3 Hz, 1 H), 6.37 (t, J =

7.6 Hz, 1 H), 7.27-7.37 (m, 6 H), 7.50-7.55 (m, 2 H), 7.62-7.65 (m, 2 H); 13C NMR

(100MHz, CDCl3): δ 31.9, 34.4, 51.8, 52.4, 86.4, 95.5, 123.3, 124.1, 125.9, 126.8,

127.5, 128.2, 130.4, 131.4, 135.2, 137.9, 169.1; High-resolution MS, calcd for

C25H24O4: 388.1675. Found m/z (relative intensity): 389 (M++1, 28), 388.1689 (M+,

100), 373 (6), 357 (92), 329 (22).

Dimethyl 2-[(2E,5E)-6,8-bis(trimethylsilyl)octa-2,5-dien-7-ynyl]malonate: (7ch)


7ch as a color less oil.

TMS CO2Me

CO2Me

TMS

Dimethyl 2-[(2E,5E)-6,8-bis(trimethylsilyl)octa-2,5-dien-7-ynyl]malonate (7ch): IR

(neat) 3003 (m), 2957 (s), 2899 (s), 2847(m), 2127 (s), 1738 (s), 1582 (m), 1435 (s),

52

1250 (s), 1155 (s), 970 (m), 841 (s), 758 (m), 698 (m) cm-1; 1H NMR (400MHz, CDCl3)

δ 0.13 (s, 9 H), 0.18 (s, 9 H), 2.60 (td, J = 7.6, 0.9 Hz, 2 H), 3.06 (td, J = 6.8, 1.0 Hz 2

H), 3.42 (t, J = 7.6 Hz, 1 H), 3.72 (s, 6 H), 5.42 (dt, J = 15.3, 7.6 Hz, 1 H), 5.53 (dt, J =

15.3, 6.8 Hz, 1 H), 6.00 (t, J = 6.8 Hz, 1 H); 13C NMR (100MHz, CDCl3) δ -2.0, 0.3,

32.0, 35.8, 51.9, 52.4, 102.8, 104.1, 125.7, 126.7, 130.5, 148.7, 169.2; High-resolution

MS, calcd for C19H32O4Si2: 380.1841. Found m/z (relative intensity): 381 (M++1, 31),

380.1841 (M+, 100), 365 (44), 349 (8).

Dimethyl 2-[(E)-4-(trimethylsilyl)-2-vinylpent-3-enyl]malonate: (6ch)


6ch as a color less oil.

CO2Me

CO2Me

TMS

Dimethyl 2-[(E)-4-(trimethylsilyl)-2-vinylpent-3-enyl]malonate (6ch): IR (neat)

3074 (m), 3003 (m), 2955 (s), 2855 (s), 1740 (s), 1616 (m), 1437 (s), 1248 (s), 1157 (s),

1024 (m), 837 (s), 752 (m), 691 (m) cm-1; 1H NMR (400MHz, CDCl3) δ 0.05 (s, 9 H),

1.65 (d, J = 1.7 Hz, 3 H), 1.96 (t, J = 7.4 Hz 1 H), 2.02 (t, J = 7.4 Hz, 1 H), 3.14 (dtd, J

= 8.7, 7.4, 7.2 Hz, 1 H), 3.38 (t, J = 7.4 Hz, 1 H), 3.72 (s, 3 H), 3.73 (s, 3 H), 4.99 (dd, J

= 17.3, 1.3 Hz, 1 H), 5.00 (dd, J = 10.0, 1.3 Hz, 1 H), 5.45 (dq, J = 8.7, 1.7 Hz, 2 H),

5.64 (ddd, J = 17.3, 10.0, 7.2 Hz, 1 H); 13C NMR (100MHz, CDCl3) δ -2.1, 14.6, 33.6,


53

C15H26O4Si: 298.1600. Found m/z (relative intensity): 299 (M++1, 18), 298.1591 (M+,

45), 283 (100), 267 (64).

54

References

(1) (a) Jun, C.-H. Chem. Soc. Rev. 2004, 33, 610.

(b) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. Rev. 2007, 107, 3117.

(2) (a) Suginome, M.; Matsuda, T.; Yoshimoto, T.; Ito, Y. Organometallics 2002, 21,

1537.

(b) Zuo, G.; Louie, J. Angew. Chem. Int. Ed. 2004, 43, 2277.

(c) Zuo, G.; Louie, J. J. Am. Chem. Soc. 2005, 127, 5798.

(d) Liu, L.; Montgomery, J. J. Am. Chem. Soc. 2006, 128, 5348.

(e) Ogoshi, S.; Nagata, M.; Kurosawa, H. J. Am. Chem. Soc. 2006, 128, 5350.

(f) Bowman, R. K.; Jonson, J. S. Org. Lett. 2006, 8, 573.

(g) Kimura, M.; Tamaru, Y. Topics in Current Chemistry 2007, 279, 173.

(h) Ogata, K.; Atsuumi, Y.; Shimada, D.; Fukuzawa, S.-i. Angew. Chem. Int. Ed.

2011, 50, 5896.

(3) (a) Kimura, M.; Ezoe, A.; Shibata, K.; Tamaru, Y. J. Am. Chem. Soc. 1998, 120,

4033.

(b) Kimura, M.; Ezoe, A.; Tanaka, S.; Tamaru, Y. Angew. Chem. Int. Ed. 2001,

40, 3600.

(c) Kimura, M.; Ezoe, A.; Mori, M.; Iwata, K.; Tamaru, Y. J. Am. Chem. Soc.

2006, 128, 8559.

55

(d) Tamaru, Y.; Kimura, M. Organic Syntheses 2006, 83, 88.

(4) (a) Kimura, M.; Fujimatsu, H.; Ezoe, A.; Shibata, K.; Shimizu, M.; Matsumoto,

S.; Tamaru, Y. Angew. Chem. Int. Ed. 1999, 38, 397.

(b) Kimura, M.; Miyachi, A.; Kojima, K.; Tanaka, S.; Tamaru, Y. J. Am. Chem.

Soc. 2004, 126, 14360.

(5) (a) Kimura, M.; Ezoe, A.; Mori, M.; Tamaru, Y. J. Am. Chem. Soc. 2005, 127,

201.

(b) Kojima, K.; Kimura, M.; Tamaru, Y. Chem. Commun. 2005, 4717.

(c) Kimura, M.; Kojima, K.; Tatsuyama, Y.; M.; Tamaru, Y. J. Am. Chem. Soc.

2006, 128, 6332.

(d) Kimura, M.; Mori, M.; Mukai, R.; Kojima, K.; Tamaru, Y. Chem. Commun.

2006, 3813.

(e) Kojima, K.; Kimura, M.; Ueda, S.; Tamaru, Y. Tetrahedron 2006, 62, 7512.

(6) (a) Ikeda, S.-i.; Cui, D.-M.; Sato, Y. J. Org. Chem. 1994, 59, 6877.

(b) Ikeda, S.-i.; Miyashita, H.; Sato, Y. Organometallics 1998, 17, 4316.

(c) Cui, D.-M.; Tsuzuki, T.; Miyake, K.; Ikeda, S.-i.; Sato, Y. Tetrahedron 1998,

54, 1063.

56

(7) Ikeda, S.; Obara, H.; Tsuchida, E.; Shirai, N.; Odashima, K. Organometallics 2008, 27,

1645.

(8) (a) Giacomelli, G.; Marcacci, F.; Caporusso, A. M.; Lardicci, L. Tetrahedron

Lett. 1979, 20, 3217.

(b) Ogoshi, S.; Ueta, M.; Oka, M.; Kurosawa, H. Chem. Commun. 2004, 2732.

(c) Nakao, Y.; Shirakawa, E.; Tsuchimoto, T.; Hiyama, T. J. Organomet. Chem.

2004, 689, 3701.

(d) Takahashi, G.; Shirakawa, E.; Tsuchimoto, T.; Kawakami, Y. Adv. Synth.

Catal. 2006, 348, 837.

(9) Mori, T.; Nakamura, T.; Onodera, G.; Kimura, M. Synthesis 2012, 44, 2333.

(10) Parsons, A. T.; Campbell, M. J.; Johnson, J. S. Org. Lett. 2008, 10, 2541.

57

Chapter 2

Multicomponent Coupling Reaction via Azanickelacycle:

Ni-Catalyzed Homoallylation of Polyhydroxy N,O-Acetals with

Conjugated Dienes Promoted by Triethylbrane

Summary: In the presence of Ni-catalyst and triethylborane, N,O-acetals prepared from

glycolaldehyde and glyceraldehyde with primary amines in situ underwent homo-

allylation with conjugated dienes to provide 2-amino-5-hexenols in high regio- and

stereoselectivity. Under similar reaction conditions, N,O-acetals from carbohydrates

with primary amines provided the corresponding polyhydroxy-bishomoallylamines in

good to reasonable yields.

R+

cat. Ni(0)

Et3B+R1NH2

OHO

R2 R HN R1

OHR2n n

R+

cat. Ni(0)

Et3B+R1NH2

RR3

HN R1

OHO

O

OH

HO R3

R3

58

Introduction

Ni-catalyzed C–C bond formation is a useful strategy for organic syntheses1.

Cross-coupling of organometallic compounds with aromatic halides, as well as

allylation and vinylation of carbonyls, is widely utilized for the synthesis of

physiologically active molecules and fine chemicals2. Compared to catalytically C–C

bond transformations involving allylation and vinylation, homoallylation of carbonyls

providing bis-homoallyl alcohols have serious limitations, which may be due to the

unavailability and low stability of homoallyl anion species that can react with

electrophiles3.

Recently, a Ni catalyst was developed that could promote the homoallylation of

benzaldehyde with a wide variety of 1,3-dienes in the presence of triethylborane to

afford bis-homoallyl alcohols (Eq. 1)4. For these processes, isoprene reacts at the C1

position with an aromatic aldehyde to give 3-methyl-4-penten-1-ol with excellent

1,3-anti stereoselectivity. A similar homoallylation to produce aliphatic aldehydes

and ketones was successful using diethylzinc instead of triethylborane5. Results

indicated that diethylzinc functions as a more effective promoter than triethylborane

for the homoallylation of aliphatic aldehydes and ketones. In contrast, triethylborane

is compatible with water and alcohols, and even promotes homoallylation of aqueous

aldehyde (e.g., glutaraldehyde) and ω-hydroxyaldehyde (lactol) with conjugated dienes

to afford ω-hydroxyhomoallyl alcohols (Eq. 2)6. Thus, triethylborane and diethylzinc

59

can be used in a complementary manner to accelerate homoallyation of carbonyl

compounds.

In addition, Ni-catalyzed homoallylation of aldimines prepared from aldehydes

and primary amines in situ with conjugated dienes provided bis-homoallylamines in

high regio- and stereoselectivity (Eq. 3)7. Thus, the C1 position of isoprene reacts

with aldimines to afford 3-methyl-4-pentenylamines with excellent 1,3-syn

stereoselectivity, compared to 1,3-anti stereoselectivity when using aldehydes.

This report describes a similar reaction system involving a Ni catalyst and

cat. Ni(0)

Et3Bn = 1 or 2

+OHO

OH

OHn n

+cat. Ni(0)

Et3B+R1NH2

R2

HN R1

+cat. Ni(0)

Et3B or Et2ZnRCHO

R

OH

1,3-anti selective

R2CHO

1,3-anti selective

1,3-syn selective

(1)

(2)

(3)

60

triethylborane that was extended successfully to the homoallylation of N,O-acetals

prepared from cyclic hemiacetals and primary amines to provide ω-hydroxy-

bishomoallylamines in high regio- and stereoselectivity (Eq. 4). In similar catalytic

reaction systems, N,O-acetals from carbohydrates with primary amines gave the

polyhydroxybishomoallylamines in good to reasonable yields.

R+

cat. Ni(0)

Et3B+R1NH2 (4)

OHO n

R HN

OHn

R1

61


Results of reactions of isoprene with N,O-acetals prepared from cyclic hemiacetals

and p-methoxyaniline are summarized in Table 1. Reactions were conducted at room

temperature using isoprene, Ni(cod)2 catalyst, triethylborane, and N,O-acetals under

nitrogen atmosphere. Isoprene reacted at the C1 position with N,O-acetals and

underwent homoallylation to provide hydroxybishomoallylamines. 2-Hydroxytetra-

hydrofuran provided 1-(3-hydroxypropyl)-3-methyl-4-pentenylamine 4a in reasonable

yield along with a mixture of diastereomers in a 5:1 ratio (entry 1, Table 1). 5-Naph-

thyl-2-hydroxytetrahydrofuran provided the desired product 4b in 71% yield along with

two diastereomers in a 2:1 ratio (entry 2, Table 1). 5-Methyl-5-n-hexyl-2-hydroxy-

tetrahydrofuran participated in the homoallylation to afford hydroxylamine 4c, which

possessed a tertiary alcohol moiety (entry 3, Table 1). Six-membered cyclic hemia-

cetals could be used for homoallylation to form amino alcohols 4d and 4e in 6:1 and 4:1

ratios, respectively (entries 4-5, Table 1). 2-Hydroxychroman served as an N,O-acetal

precursor by treatment with a primary amine to provide o-aminoalkyl phenol 4f, (entry

6, Table 1). N-Boc-2-hydroxypiperidine acted as an aldimine in the presence of

p-methoxyaniline to participate in the coupling reaction with isoprene to provide

2-butenylaminobishomoallylamine 4g (entry 7, Table 1). Seven-membered cyclic

hemiacetal underwent a similar homoallylation to provide 1-(5-hydroxypentyl)-3-

methyl-4-pentenylamine 4h in reasonable yield (entry 8, Table 1).

62

Table 1. Scope of the Nickel-Catalyzed Homoallylation of N,O-Acetals with

Isoprenea

entry hemiacetal product yield of 4 (%)

[ratio]

1 3a:

4a: 58 [5:1]

2 3b:

4b: 71 [2:1]

3 3c:

4c: 59 [3:1]

4 3d:

4d: 91 [6:1]

5 3e:

4e: 69 [4:1]

6 3f:

4f: 61 [7:1]

+

cat. Ni(cod)2

Et3Bn = 1~3

+OHO n

HN

OHn

PMP

NH2

MeO

R

R

1a 2a 3

4

OHO OHHN PMP

OHO Naphtyl OHHN PMP

Naphtyl

OHO n-C6H13OH

HN PMP

n-C6H13

OHOHN PMP

OH

OHO

HN PMP

OH

OHO

HN PMP OH

63


7

3g: 4g: 41 [3:1]

8 3h:

4h: 58 [4:1]

a N,O-Acetals were prepared from cyclic hemiacetals (1 mmol) and amines (2 mmol) stirring in THF (2 mL). A solution of isoprene (4 mmol), Ni(cod)2 (0.1 mmol) in THF (2 mL) and Et3B (3.6 mmol) were introduced to the N,O-acetals, and the reaction mixture was stirred at room temperature for 24 h under nitrogen atmosphere.

Glycolaldehyde dimer is a two-carbon monosaccharide (diose) that is an important

component of biologically active molecules8. The reaction of glycolaldehyde dimer

as an N,O-acetal precursor with conjugated dienes to furnish 1-hydroxymethyl-

4-pentenylamines also was examined. Results using various conjugated dienes and

N,O-acetals prepared from primary amines and glycolaldehyde dimer are summarized

in Table 2. 1,3-Butadiene reacted with N,O-acetal prepared from p-methoxyaniline to

yield 47% of 1-hydroxymethyl-4-pentenylamine 6aa along with 23% of the internal

olefin isomer 6’aa (entry 1, Table 2). N,O-Acetal from aniline underwent homo-

allylation with isoprene to provide 1-hydroxymethyl-3-methyl-4-pentenylamine 6bb in

reasonable yield with a diastereomeric mixture in a 8:1 ratio (entry 2, Table 2).

p-Methoxy and o-methoxyaniline participated in similar homoallylations to provide

hydroxyamines 6ba and 6bc, respectively, with high stereoselectivity in an 8:1 ratio

NHOBoc

HNPMP

NHBoc

OHO

HN PMP

OH

64

Table 2. Scope of the Nickel-Catalyzed Homoallylation of N,O-Acetals,

Prepared from Glycolaldehyde Dimer, with Isoprenea

entry diene: R amine: R1 yield of 6 (%) [ratio]

1 1a: H 2a 6aa: 47b

2 1b: Me 2b: phenyl 6bb: 64 [8:1]

3 1b: Me 2a 6ba: 59 [single]

4 1b: Me 2c: o-methoxyphenyl 6bc: 64[8:1]

5 1b: Me 2d: p-bromophenyl 6bd: 50 [single]

6 1b: Me 2e: benzyl intractable mixture

7 1c: -(CH2)2CH=CMe2 2a 6ca: 49 [single]

aN,O-Acetals were prepared from glycolaldehyde dimer (1 mmol) and amines (4 mmol) stirring in THF (2 mL). A solution of conjugated diene (8 mmol), Ni(cod)2 (0.1 mmol) in THF (2 mL) and Et3B (6 mmol) were introduced to the N,O-acetals, and the reaction mixture was stirred at room temperature for 48 h under N2. b Internal olefin isomer 6’aa was obtained in 23%.

R+

cat. Ni(cod)2

Et3B

+

ROH

HN R11 2

6

R1NH2O

OHO

OH5a

65

and as a single isomer, respectively (entries 3-4, Table 2). p-Bromoaniline underwent

homoallylation effectively to afford the desired hydroxylamine 6bd as the sole

product (entry 5, Table 2). Benzylamine yielded an intractable mixture; the expected

reaction was not observed (entry 6, Table 2). Myrcene also participated in

homoallylation with N,O-acetal to produce the corresponding hydroxylamine 6ca as a

single product (entry 7, Table 2).

Glyceraldehyde is a triose monosaccharide generally used for the enzymatic

synthesis of D-fructose and L-sorbose with aldolases9. The glyceraldehyde can serve

as an important electrophilic component for coupling reactions to form a physiologica-

lly active molecules. The Ni-catalyzed homoallylation of glyceraldehyde dimer was

accomplished using primary amines and conjugated dienes in the presence of

triethylborane (Table 3). In this reaction, N,O-acetals prepared from glyceraldehyde

dimer and primary amines in DMF via azeotropic distillation underwent homo-

allylation with conjugated dienes to furnish dihydroxybishomoallylamines. 1,3-Buta-

diene reacted with N,O-acetal from p-methoxyaniline to provide 1-(1,2-dihydroxy-

ethyl)-4-pentenyl-amine 8aa in 56% yield along with the internal olefin isomer 8’aa in

17% yield (entry 1, Table 3). N,O-Acetal from aniline participated in homoallylation

with isoprene to provide 1-(1,2-dihydroxyethyl)-3-methyl-4-pent-enylamine 8bb in

62% yield in a 2:1 ratio of diastereomers (entry 2, Table 3). p-Methoxyaniline gave a

similar homoallylation product 8ba with a mixture of diastereoisomers in a 2:1 ratio

(entry 3, Table 3). Benzylamine provided an intractable mixture in the same way as

66


Prepared from Glyceraldehyde Dimer, with Isoprenea

entry diene: R amine: R1 yield of 8 (%) [ratio]

1 1a 2a 8aa: 56 [3:1]

2 1b 2b 8bb: 62 [2:1]

3 1b 2a 8ba: 69 [2:1]

4 1b 2e intractable mixture

5 1c 2a 8ca: 64 [2:1]

a N,O-Acetals were prepared from glyceraldehyde dimer (1 mmol) and amines (4 mmol) in DMF (2 mL) via azeotropic distillation. A solution of conjugated diene (8 mmol), Ni(cod)2 (0.1 mmol) in THF (2 mL) and Et3B (6 mmol) were introduced to the residual oil of N,O-acetals, and then the reaction mixture was stirred at room temperature for 48 h under N2. b Internal olefin isomer 8’aa was obtained in 17% with 3:1 diastereoisomeric ratio.

R+

cat. Ni(cod)2

Et3B

+

R HN R11 2

8

R1NH2O

OHO

OH7a

OH

OH

OHOH

67

the result of glycolaldehyde with aliphatic amine (entry 4, Table 3). Myrcene

underwent homoallylation with N,O-acetal to produce the corresponding

hydroxylamine 8ca in reasonable yield with diastereomers in a 2:1 ratio, as well as

isoprene (entry 5, Table 3).

Next, homoallylation of N,O-acetals from carbohydrates, such as 2-deoxy-

D-ribose, D-ribose, and 2-deoxy-D-glucose, was investigated. Various N,O-acetals

prepared from carbohydrates and aromatic amines underwent homoallylation with

conjugated dienes in one pot to provide polyhydroxyamines (Table 4). 1,3-Butadiene

reacted with N,O-acetal from 2-deoxy-D-ribose and p-methoxyaniline to afford the

homoallylation product 9aa in moderate yield along with the allylation product as a

diastereoisomeric mixture of internal olefin isomers 9’aa (entry 1, Table 4). Isoprene

reacted at the C1 position with N,O-acetals derived from 2-deoxy-D-ribose and various

aromatic amines to provide the desired polyhydroxyamines 9ba-9bg as mixtures of

two diastereomers in a nearly 2:1 ratio (entries 2-6, Table 4). Myrcene also

participated in homoallylation as a conjugated diene and afforded the desired product

9ca in 56% in a 1:1 ratio (entry 7, Table 4). Since D-ribose and 2-deoxy-D-glucose

are insoluble in THF, a series of N,O-acetals with D-ribose and 2-deoxy-D-glucose

were prepared from amines in DMF via azeotropic distillation, and were used for

homoallylation with isoprene to produce the expected polyhydroxyamines 10ba and

11ba, respectively (entries 8 and 9, Table 4). Although carbohydrates were expected

68


Prepared from Carbohydrate, with Isoprenea

entry carbohydrate diene: R amine: R1 yield of 9, 10 and

11 (%) [ratio]

1 2-deoxy-D-ribose 1a 2a 9aa: 27 [1:1]b

2 2-deoxy-D-ribose 1b 2a 9ba: 74 [2:1]

3 2-deoxy-D-ribose 1b 2c 9bc: 80 [2:1]

4 2-deoxy-D-ribose 1b 2f: 3,4-dimethoxyphenyl 9bf: 58 [2:1]

5 2-deoxy-D-ribose 1b 2b 9bb: 75 [2:1]

6 2-deoxy-D-ribose 1b 2g: p-chlorophenyl 9bg: 30 [2:1]

7 2-deoxy-D-ribose 1c 2a 9ca: 56 [1:1]

8 D-ribose 1b 2a 10ba: 57 [2:1]

9 2-deoxy-D-glucose 1b 2a 11ba: 64 [1:1]

a N,O-Acetals were prepared from carbohydrate (1 mmol) and amines (2 mmol) in THF (5 mL, entries 1-7) or DMF (5 mL, entries 8 and 9) via azeotropic distillation. A solution of conjugated diene (8 mmol), Ni(cod)2 (0.1 mmol) in THF (2 mL) and Et3B (6 mmol) were introduced to the N,O-acetals, and the reaction mixture was stirred at room temperature (entries 1-7) or 50 ˚C for 48 h (entries 8 and 9) under N2. b Internal olefin isomer 9’aa was obtained in 32% with 3:1 diastereoisomeric ratio.

R+

cat. Ni(cod)2

Et3B+

R HN R1

1 2

11

R1NH2 carbohydrate

R HN R1

10

R HN R1

9

OH

OH

OH

OH

OH

OH

OH OH

OH

OH

OH

69

to serve as carbonyl electrophiles and chiral auxiliaries to induce stereoselectivity of

the homoallylation, the consecutive homoallylations of N,O-acetals did not proceed

with high stereoselectivity.

Although all product absolute configurations have not yet been determined, a

plausible reaction mechanism based on the homoallylation of aldimines prepared from

aldehydes and primary amines with isoprene is illustrated in Scheme 17. N,O-Acetals

were readily prepared from cyclic hemiacetals with primary amines in situ, and the low

concentration of ω-hydroxyimine tautomers in equilibrium with the N,O-acetals

appeared to promote reaction with conjugated dienes (Scheme 2). As triethylborane

coordinates to the nitrogen atom of N,O-acetals as a Lewis acid, the formation of

ω-hydroxyimine tautomers might predominate over N,O-acetals. Formation of an

azanickelacycle intermediate via oxidative cyclization with isoprene and ω-hydroxy-

imine in the presence of Ni(0) catalyst results in a quasi-equatorial position of the

nitrogen atom substituent to avoid the steric repulsion toward the ω-hydroxyalkyl main

chain. As a result, the aldimine moiety assumed a diaxial configuration resulting in

1,3-syn stereoselectivity with respect to the methyl group of isoprene and amino groups.

70

Scheme 1. Ni-Catalyzed Homoallylation of N,O-Acetal with Isoprene Promoted

by Triethylborane

Scheme 2. Equilibrium between Cyclic N,O-Acetal and ω-Hydroxyamine

cat. Ni(0)

Et3B+

ORHN

HN

OH

R

OHNi N

RBEt3H

Ni N

BEt3

ROH

H

13

2

132

oxidativecyclization

Ni(0)Et3B

reductiveelimination -Ni(0)

OHNi N

RBEt2H

13

2

Et

OHHNi N

RBEt2H

13

2

OHO n + RNH2 ORHN n ORN n

H

- H2O

+ H2O

71
















JEOL JMS-DX303.


Tetrahydrofuran, toluene, and diethyl ether were dried and distilled from

benzophenone-sodium immediately prior to use under nitrogen atmosphere. DMF was

distilled over calcium chloride. Triethylborane (1 M THF, Aldrich), Ni(cod)2

(KANTO Kagaku) were used without further purification. Isoprene, myrcene,

72

glycolaldehyde dimmer, glyceraldehyde dimer, 2-deoxy-D-ribose, D-ribose,

2-deoxy-D-glucose, aniline, p-methoxyaniline, o-methoxyaniline, p-bromoaniline,

benzylamine were purchased and used without purification. 1,3-Butadiene (Tokyo

Kasei Kogyo Co., Ltd) was purchased, and was liquefied by cooling at -78 ˚C (dry

ice/isopropanol) prior to use under argon atmosphere. 1,3-Butadiene could be

measured by syringe kept cool in the freezer as well beforehand, and then was

introduced into the reaction mixture at room temperature. Tetrahydrofuran-2-ol,

tetrahydro-2H-pyran-2-ol, oxepane-2-ol, 5-(naphthalen-2-yl)tetrahydrofuran-2-ol, and

all of these substrates in Table 1 were prepared according to the literature10.

73

General procedure 1: for the Nickel-catalyzed homoallylation of N,O-acetals with

isoprene (entry 4, Table 1)



connected into nitrogen balloon), and a Teflon-coated magnetic stir bar was charged.

A solution of tetrahydro-2H-pyran-2-ol (102 mg, 1 mmol) and p-anisidine (246 mg, 2

mmol) in dry THF (2 mL) was stirred overnight under nitrogen. A mixture of Ni(cod)2

(27.5 mg, 0.1 mmol) and isoprene (400 µL, 4 mmol) dissolved in THF (2 mL) and

triethylborane (3.6 mmol, 1.0 M THF solution) were successively added to the

N,O-acetal solution via the dropping funnel over a period of 10 min. The reaction

mixture was stirred at room temperature for 24 h and monitored by TLC. After the

reaction was completed, the reaction mixture was cooled to 0 ˚C, and then poured into

ice-water. The resulting solution was diluted with 30 mL of EtOAc and carefully

washed with 2 M HCl, with sat. NaHCO3, and brine. The aqueous layer was extracted

with 30 mL of EtOAc. The combined organic phases were dried (MgSO4) and

concentrated in vacuo, and the residual oil was subjected to column chromatography

over silica gel (eluent; hexane/EtOAc = 2/1 v/v) to afford 4d (258 mg, 91%; Rf = 0.30;

hexane/EtOAc = 4/1 v/v) in a 6:1 ratio.

74

5-[(4-Methoxyphenyl)amino]-7-methylnon-8-en-1-ol: (4d)

5-[(4-Methoxyphenyl)amino]-7-methylnon-8-en-1-ol (4d): (a mixture of major and

minor isomers in a ratio of 6:1): IR (neat) 3368 (s), 2934 (s), 1514 (m), 1458 (s), 1236

(s), 1040 (s), 820 (s) cm-1; 1H NMR (400 MHz, CDCl3, major-isomer) δ 1.00 (d, J = 6.6

Hz, 3 H), 1.37 – 1.58, (m, 8 H), 2.33 – 2.38 (m, 1 H), 3.31 (m, 1 H), 3.62 (t, J = 6.3

Hz, 2 H), 3.73 (s, 3 H), 4.92 (dd, J = 10.4, 1.1 Hz, 1 H), 4.93 (dd, J = 17.0, 1.1 Hz, 1 H),

5.65 (ddd, J = 17.0, 10.4, 8.1 Hz, 1 H), 6.52 (d, J = 8.9 Hz, 2 H), 6.74 (d, J = 8.9 Hz, 2

H); 13C NMR (100 MHz, CDCl3, major-isomer) δ 21.1, 22.0, 32.8, 35.0, 35.2, 42.5,

52.1, 55.8, 62.8, 113.2, 114.4, 114.9, 142.1, 144.3, 151.6; 1H NMR (400 MHz, CDCl3,

minor-isomer) δ 0.98 (d, J = 6.8 Hz, 3 H), 1.37 – 1.58, (m, 8 H), 2.33 – 2.38 (m, 1 H),

3.31 (m, 1 H), 3.61 (t, J = 6.5 Hz, 2 H), 3.74 (s, 3 H), 4.92 (dd, J = 10.4, 1.1 Hz, 1 H),

4.93 (dd, J = 17.0, 1.1 Hz, 1 H), 5.65 (ddd, J = 17.0, 10.4, 8.1 Hz, 1 H), 6.52 (d, J = 8.9

Hz, 2 H), 6.74 (d, J = 8.9 Hz, 2 H); 13C NMR (100 MHz, CDCl3, minor-isomer) δ 21.1,

21.9, 32.8, 35.0, 35.2, 42.1, 52.1, 55.8, 62.8, 113.2, 114.2, 114.8, 142.1, 144.3, 151.6;

HRMS, calcd for C17H27 NO2: 277.2018. Found m/z (relative intensity): 278.2001

(M++1, 1), 277.2014 (M+, 2), 260.1983 (13), 204.1406 (100).

(4S,6S)-4-(4-methoxyphenylamino)-6-methyloct-7-en-1-ol: (4a)

HN PMP

OH

75

Following General Procedure 1, Purification by flash column chromatography.

(4S,6S)-4-(4-methoxyphenylamino)-6-methyloct-7-en-1-ol (4a): (a mixture of major

and minor isomers in a ratio of 5:1): IR (neat) 3310 (s) , 3071 (s), 2924 (s), 1643 (m),

1458 (s), 1065 (s), 910 (s), 741 (s) cm-1; 1H NMR (400 MHz, CDCl3, major-isomer) δ

0.99 (d, J = 6.7 Hz, 3 H), 1.60 – 1.69 (m, 6 H), 2.35 (qm, J = 6.7 Hz, 1 H), 2.52 (br,

1H), 3.32 (m, 1 H), 3.60 (t, J = 6.1 Hz, 2 H), 3.73 (s, 3 H), 4.92 (dm, J = 10.7 Hz, 1 H),

4.93 (dd, J = 16.9, 1.0 Hz, 1 H), 5.65 (ddd, J = 16.9, 10.7, 8.0 Hz, 1 H) , 6.54 (dd, J =

6.6, 2.2 Hz, 2 H), 6.75 (m, 2 H); 13C NMR (100 MHz, CDCl3, major-isomer) δ 21.0,

29.3, 32.0, 35.0, 42.5, 54.0, 55.8, 62.9, 63.0, 113.2, 114.9, 115.0, 115.4, 141.5, 141.8,

144.3; 1H NMR (400 MHz, CDCl3, minor-isomer) δ 0.99 (d, J = 6.7 Hz, 3 H), 1.60 –

1.69 (m, 6 H), 2.35 (qm, J = 6.7 Hz, 1 H), 2.52 (br, 1H), 3.32 (m, 1 H), 3.60 (t, J = 6.1

Hz, 2 H), 3.73 (s, 3 H), 4.93 (dd, J = 16.9, 1.0 Hz, 1 H), 4.98 (dm, J = 17.1 Hz, 1 H),

5.65 (ddd, J = 16.9, 10.7, 8.0 Hz, 1 H) , 6.54 (dd, J = 6.6, 2.2 Hz, 2 H), 6.75 (m, 2 H);

13C NMR (100 MHz, CDCl3, minor-isomer) δ 20.8, 29.2, 32.0, 35.0, 45.3, 54.0, 55.8,

62.9, 63.0, 113.2, 114.8, 115.0, 115.4, 141.6, 141.8, 144.1; HRMS, calcd for

C16H25NO2: 263.1885. Found m/z (relative intensity): 264.1882 (M++1, 18), 263.1850

(M+, 97), 205.1411 (15), 204.1394 (100).

(4S,6S)-4-(4-methoxyphenylamino)-6-methyl-1-(naphthalenyl) octen-7-ol: (4b)


OHHN PMP

76

(4S,6S)-4-(4-methoxyphenylamino)-6-methyl-1-(naphthalenyl) octen-7-ol (4b): (a

mixture of major and minor isomers in a ratio of 2:1): IR (neat) 3366 (s), 2930 (s),

2359 (m), 1506 (s), 1238 (s), 1040 (s), 820 (s), 750 (s) cm-1; 1H NMR (400 MHz,

CDCl3, major-isomer) δ 0.95 (d, J = 6.8 Hz, 3 H), 1.38 – 1.94 (m, 6 H), 2.29 (qm, J =

6.8 Hz, 1 H), 3.11 (br, 1 H), 3.32 (br q, J = 5.9 Hz, 1 H), 3.71 (s, 3 H), 4.78 – 4.82 (m,

1 H), 4.88 (dd, J = 18.3, 1.9 Hz, 1 H), 4.89 (dd, J = 10.8, 1.9 Hz, 1 H), 5.59 (ddd, J =

18.3, 10.8, 8.3 Hz, 1 H), 6.53 (d, J = 8.9 Hz, 2 H), 6.70 (dd, J = 8.9, 1.0 Hz, 2 H), 7.39

– 7.82 (m, 7 H); 13C NMR (100 MHz, CDCl3, major-isomer) δ 20.9, 31.7, 35.0, 35.5,

42.3, 53.0, 55.7, 74.5, 113.2, 114.8, 115.3, 123.9, 124.4, 125.6, 125.7, 125.9, 126.0,

127.5, 128.0, 132.8, 133.1, 141.9, 144.1, 152.2; 1H NMR (400 MHz, CDCl3,

minor-isomer) δ 0.92 (d, J = 6.8 Hz, 3 H), 1.38 – 1.94 (m, 6 H), 2.29 (qm, J = 6.8 Hz, 1

H), 3.11 (br, 1 H), 3.32 (br q, J = 5.9 Hz, 1 H), 3.72 (s, 3 H), 4.83 (dm, J = 18.3 Hz, 1

H), 4.88 (dd, J = 18.3, 1.9 Hz, 1 H), 4.89 (dd, J = 10.8, 1.9 Hz, 1 H), 5.58 – 5.66 (m, 1

H), 6.53 (d, J = 8.9 Hz, 2 H), 6.70 (dd, J = 8.9, 1.0 Hz, 2 H), 7.39 – 7.82 (m, 7 H); 13C

NMR (100 MHz, CDCl3, minor-isomer) δ 20.9, 31.2, 34.9, 35.7, 42.3, 52.7, 55.7, 74.4,

113.2, 114.8, 115.2, 124.0, 124.4, 125.6, 125.7, 125.9, 126.0, 127.5, 128.1, 132.6,

133.1, 141.3, 144.1, 152.1; HRMS, calcd for C26H31NO2: 389.2355. Found m/z

(relative intensity): 389.2340 (M+, 100).

OHHN PMP

Naphtyl

77

10-(4-methoxyphenylamino)-7,12-dimethyl-13-tetradecen-7-ol: (4c)


10-(4-methoxyphenylamino)-7,12-dimethyl-13-tetradecen-7-ol (4c): (a mixture of

major and minor isomers in a ratio of 3:1): IR (neat) 3379 (s), 2932 (s), 2359 (m), 1639

(s), 1514 (s), 1238 (s), 1043 (s), 912 (s), 818 (s) cm-1; 1H NMR (400 MHz, CDCl3,

major-isomer) δ 0.88 (t, J = 6.4 Hz, 3 H), 0.96 (d, J = 6.8 Hz, 3 H), 1.12 –1.26 (m, 8 H),

1.42 (br, 3 H), 1.49 – 1.69 (m, 8 H), 2.29 (qm, J = 6.8 Hz, 1 H), 3.25 – 3.33 (m, 1 H),

3.74 (s, 3 H), 4.91 (dd, J = 10.7, 1.5 Hz, 1 H), 4.92 (dd, J = 17.5, 1.5 Hz, 1 H), 5.63

(ddd, J = 17.5, 10.7, 8.0 Hz, 1 H) , 6.69 – 6.72 (m, 2 H), 6.75 (d, J = 9.3 Hz, 2 H); 13C

NMR (100 MHz, CDCl3, major-isomer) δ 14.1, 20.7, 20.9, 22.6, 26.9, 27.6, 29.8, 31.8,

35.0, 37.4, 37.6, 41.9, 55.6, 55.7, 72.6, 113.3, 114.0, 116.8, 143.4, 143.9, 144.0; 1H

NMR (400 MHz, CDCl3, minor-isomer) δ 0.88 (t, J = 6.4 Hz, 3 H), 0.97 (d, J = 6.8 Hz,

3 H), 1.12 –1.26 (m, 8 H), 1.42 (br, 3 H), 1.49 – 1.69 (m, 8 H), 2.29 (qm, J = 6.8 Hz, 1

H), 3.25 – 3.33 (m, 1 H), 3.74 (s, 3 H), 4.91 (dd, J = 10.7, 1.5 Hz, 1 H), 4.92 (dd, J =

17.5, 1.5 Hz, 1 H), 5.63 (ddd, J = 17.5, 10.7, 8.0 Hz, 1 H) , 6.69 – 6.72 (m, 2 H), 6.75

(d, J = 9.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3, minor-isomer) δ 14.1, 20.8, 20.9,

22.6, 26.8, 27.6, 29.8, 31.8, 35.0, 37.4, 37.6, 41.9, 55.6, 55.7, 72.7, 113.4, 114.0, 116.7,

143.5, 143.9, 144.0; HRMS, calcd for C23H39NO2: 361.2981. Found m/z (relative

intensity): 361.2969 (M+, 100).

OHHN PMP

n-C6H13

78

(5S,7S)-5-(4-methoxyphenylamino)-3,3,7-trimethylnonen-8-ol (4e)


(5S,7S)-5-(4-methoxyphenylamino)-3,3,7-trimethylnonen-8-ol (4e): (a mixture of

major and minor isomers in a ratio of 4:1): IR (neat) 3373 (s), 2932 (s), 2359 (m), 1732

(s), 1514 (s), 1234 (s), 1042 (s), 818 (s) cm-1; 1H NMR (400 MHz, CDCl3,

major-isomer) δ 0.94 (s, 6 H), 0.97 (d, J = 6.8 Hz, 3 H), 1.21 – 1.70(m, 6 H), 2.28 (qm,

J = 6.8 Hz, 1 H), 3.02 (br, 1 H),3.34 (m, 1 H), 3.69 (s, 3 H), 3.66 – 3.76 (m, 2 H), 4.98

(dd, J = 17.7, 1.8 Hz, 1 H), 4.99 (dd, J = 10.0, 1.8 Hz, 1 H), 5.67 (ddd, J = 17.7, 10.0,

8.3 Hz, 1 H), 6.55 (br, 2 H), 6.75 (br d, J = 8.3 Hz, 2 H); 13C NMR (100 MHz, CDCl3,

major-isomer) δ 20.1, 21.6, 28.4, 28.5, 32.7, 44.5, 47.5, 47.9, 49.3, 55.0, 59.6, 113.6,

114.9, 115.0, 144.1, 144.7, 152.0; 1H NMR (400 MHz, CDCl3, minor-isomer) δ 0.95 (s,

6 H), 0.99 (d, J = 6.6 Hz, 3 H), 1.21 – 1.70(m, 6 H), 2.28 (qm, J = 6.8 Hz, 1 H), 3.02

(br, 1 H),3.34 (m, 1 H), 3.67 (s, 3 H), 3.66 – 3.76 (m, 2 H), 4.92 (dd, J = 10.2, 0.8 Hz,

1 H), 4.95 (dd, J = 16.9, 0.8 Hz, 1 H), 5.67 (ddd, J = 17.7, 10.0, 8.3 Hz, 1 H), 6.55 (br,

2 H), 6.75 (br d, J = 8.3 Hz, 2 H); 13C NMR (100 MHz, CDCl3, minor-isomer) δ 20.1,

21.6, 28.4, 28.5, 32.6, 44.3, 47.5, 47.9, 49.3, 55.0, 59.6, 113.6, 114.8, 115.0, 144.1,

144.7, 152.0; HRMS, calcd for C19H31NO2: 305.2355. Found m/z (relative intensity):

306.2373 (M++1, 9), 305.2337 (M+, 44), 237.1655 (18), 236.1608 (100), 235.1535

(19).

HN PMP

OH

79

2-((3S,5S)-3-(4-methoxyphenylamino)-5-methyl-6-heptenyl)phenol (4f)


2-((3S,5S)-3-(4-methoxyphenylamino)-5-methyl-6-heptenyl)phenol (4f): (a mixture

of major and minor isomers in a ratio of 7:1): IR (neat) 3308 (s), 2930 (s), 1583 (m),

1506 (s), 1236 (s), 1040 (s), 822 (s), 754 (s) cm-1; 1H NMR (400 MHz, CDCl3,

major-isomer) δ 0.84 (d, J = 6.8 Hz, 3 H), 1.11 – 1.68 (m, 4 H), 2.20 (qm, J = 6.8 Hz, 1

H), 2.65 – 2.71 (m, 2 H), 2.88 – 2.95 (m, 1 H), 3.13-3.29 (m, 1 H), 3.75 (s, 3 H), 4.86

(dd, J = 10.8, 0.8 Hz, 1 H), 4.87 (dd, J = 16.7, 0.8 Hz, 1 H), 5.57 (ddd, J = 16.7, 10.8,

7.8 Hz, 1 H) , 6.78 (d, J = 8.6 Hz, 2 H), 6.84 (d, J = 8.6 Hz, 2 H), 6.73 – 6.92 (m, 2 H),

7.06 – 7.12 (m, 2 H); 13C NMR (100 MHz, CDCl3, major-isomer) δ 20.2, 26.2, 34.8,

35.3, 40.0, 53.3 , 55.6, 55.7, 112.9, 114.8, 116.3, 120.3, 127.2, 127.3, 127.4, 129.9,

130.0, 144.3, 154.8; 1H NMR (400 MHz, CDCl3, minor-isomer) δ 0.89 (d, J = 6.3 Hz,

3 H), 1.11 – 1.68 (m, 4 H), 2.20 (qm, J = 6.8 Hz, 1 H), 2.65 – 2.71 (m, 2 H), 2.88 –

2.95 (m, 1 H), 3.13-3.29 (m, 1 H), 3.75 (s, 3 H), 4.86 (dd, J = 10.8, 0.8 Hz, 1 H),

4.87 (dd, J = 16.7, 0.8 Hz, 1 H), 5.57 (ddd, J = 16.7, 10.8, 7.8 Hz, 1 H) , 6.78 (d, J =

8.6 Hz, 2 H), 6.84 (d, J = 8.6 Hz, 2 H), 6.73 – 6.92 (m, 2 H), 7.06 – 7.12 (m, 2 H); 13C

NMR (100 MHz, CDCl3, minor-isomer) δ 20.2, 26.2, 34.8, 35.3, 40.0, 53.3 , 55.6, 55.7,

112.9, 114.6, 116.3, 120.6, 127.2, 127.3, 127.4, 129.9, 130.1, 144.3, 154.8; HRMS,

calcd for C21H27NO2: 325.2042. Found m/z (relative intensity): 326.2086 (M++1, 18),

HN PMP OH

80

325.2045 (M+, 78), 257.1349 (18), 256.1329 (100).

tert-butyl(5S,7S)-5-(4-methoxyphenylamino)-7-methylnon-8-enylcarbamate (4g)


tert-butyl(5S,7S)-5-(4-methoxyphenylamino)-7-methylnon-8-enylcarbamate (4g):

(a mixture of major and minor isomers in a ratio of 3:1):IR (neat) 2864 (s), 2359 (m),

1682 (s), 1539 (s), 1251 (s), 1173 (s), 910 (s), 750 (s) cm-1; 1H NMR (400 MHz,

CDCl3, major-isomer) δ 1.01 (d, J = 6.8 Hz, 3 H), 1.34 – 1.51 (m, 8 H), 1.44 (s, 9 H),

2.32 (dm, J = 7.4 Hz, 1 H), 3.11 (br, 2 H), 3.67 (br, 1 H), 4.93 (dd, J = 10.2, 1.1 Hz, 1

H), 5.01 (dd, J = 17.4, 1.1 Hz, 1 H), 5.77 (ddd, J = 17.4, 10.2, 7.4 Hz, 1 H); 13C NMR

(100 MHz, CDCl3, major-isomer) δ 20.2, 22.6, 28.4, 30.1, 35.4, 37.2, 40.4, 44.5, 70.1,

79.0, 112.6, 114.9, 155.9; 1H NMR (400 MHz, CDCl3, minor-isomer) δ 0.98 (d, J = 6.6

Hz, 3 H), 1.34 – 1.51 (m, 8 H), 1.44 (s, 9 H), 2.32 (dm, J = 7.4 Hz, 1 H), 3.11 (br, 2

H), 3.67 (br, 1 H), 4.88 (dm, J = 11.2 Hz, 1 H), 5.01 (dd, J = 17.4, 1.1 Hz, 1 H), 5.77

(ddd, J = 17.4, 10.2, 7.4 Hz, 1 H), ,; 13C NMR (100 MHz, CDCl3, minor-isomer) δ 19.8,

22.6, 28.4, 30.0, 35.4, 37.2, 40.4, 44.3, 69.8, 79.0, 112.0, 114.6, 155.9; HRMS, calcd

for C15H29NO3: 271.2147. Found m/z (relative intensity): 376.2731 (M+, 100).

(6S,8S)-6-(4-methoxyphenylamino)-8-methyldec-9-en-1-ol (4h)


HNPMP

NHBoc

81

(6S,8S)-6-(4-methoxyphenylamino)-8-methyldec-9-en-1-ol (4h): (a mixture of major

and minor isomers in a ratio of 4:1): IR (neat) 3364 (s), 2934 (s), 1614 (m), 1514 (s),

1238 (s), 1038 (s), 822 (s) cm-1; 1H NMR (400 MHz, CDCl3, major-isomer) δ 1.00 (d,

J = 6.8 Hz, 3 H), 1.21 – 1.58, (m, 10 H), 2.34 – 2.38 (m, 1 H), 3.27 – 3.32 (m, 1 H),

3.61 (t, J = 6.6 Hz, 2 H), 3.74 (s, 3 H), 4.92 (dd, J = 10.2, 0.9 Hz, 1 H), 4.93 (dd, J =

17.0, 0.9 Hz, 1 H), 5.65 (ddd, J = 17.0, 10.2, 8.1 Hz, 1 H), 6.63 (d, J = 9.1 Hz, 2 H),

6.74 (d, J = 9.1 Hz, 2 H); 13C NMR (100 MHz, CDCl3, major-isomer) δ 21.2, 25.6,

25.9, 32.8, 35.1, 35.3, 42.4, 55.8, 55.9, 62.9, 113.3, 114.9, 116.4, 139.8, 144.3, 152.8;

1H NMR (400 MHz, CDCl3, minor-isomer) δ 0.97 (d, J = 6.8 Hz, 3 H), 1.21 – 1.58, (m,

10 H), 2.34 – 2.38 (m, 1 H), 3.27 – 3.32 (m, 1 H), 3.61 (t, J = 6.4 Hz, 2 H), 3.74 (s, 3

H), 4.92 (dd, J = 10.2, 0.9 Hz, 1 H), 4.93 (dd, J = 17.0, 0.9 Hz, 1 H), 5.65 (ddd, J =

17.0, 10.2, 8.1 Hz, 1 H), 6.63 (d, J = 9.1 Hz, 2 H), 6.74 (d, J = 9.1 Hz, 2 H), ,; 13C

NMR (100 MHz, CDCl3, minor-isomer) δ 21.2, 25.6, 25.9, 32.8, 35.1, 35.3, 42.4, 55.8,

55.9, 63.1, 113.3, 114.8, 116.4, 139.8, 144.3, 152.8; HRMS, calcd for C18H29NO2:

291.2196. Found m/z (relative intensity): 292.2236 (M++1, 15), 291.2196 (M+, 65),

223.1501 (13), 222.1497 (100).

2-(4-methoxyphenylamino)-5-hexenol (6aa)


HN PMP

OH

82

2-(4-methoxyphenylamino)-5-hexenol (6aa): IR (neat) 3375 (s), 3076 (m), 2936 (s),

1639 (s), 1514 (s), 1464 (s), 1238 (s), 1038 (s), 822 (s) cm-1; 1H NMR (400 MHz,

CDCl3) δ 1.42 (quin, J = 7.5 Hz, 2 H), 2.14 (br q, J = 6.8 Hz, 1 H), 2.25 (br q, J = 6.4

Hz, 1 H), 2.69 (br, 1 H), 3.40 (m, 2 H), 3.49 (dd, J = 10.9, 6.1 Hz, 1 H), 3.51 (dd, J =

10.9, 6.1 Hz, 1 H), 3.74 (s, 3 H), 4.94 (dm, J = 9.7 Hz, 1 H), 5.00 (dt, J = 16.1,1.9 Hz,

1 H), 5.78 (ddt, J = 16.1, 9.7, 6.4 Hz, 1 H), 6.64 (dd, J = 6.6, 2.4 Hz, 2 H), 6.74 (dd, J

= 6.6, 2.4 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 28.7, 30.4, 55.8, 56.3, 64.1, 114.8,

115.7, 116.4, 137.8, 139.8, 152.7; HRMS, calcd for C13H19NO2: 221.1416. Found m/z

(relative intensity): 222.1449 (M++1, 4), 221.1401 (M+, 28), 191.1235 (14), 190.1195

(100).

(E)-2-(4-methoxyphenylamino)-4-hexenol (6’aa)


(E)-2-(4-methoxyphenylamino)-4-hexenol (6’aa): (a mixture of E- and Z- isomers in

a ratio of 1 : 2): IR (neat) 3375 (s), 3076 (m), 2936 (s), 1639 (s), 1514 (s), 1464 (s),

1238 (s), 1038 (s), 822 (s) cm-1; 1H NMR (400 MHz, CDCl3) δ 1.64 (dm, J = 7.6 Hz,

3 H), 2.02 (m, 2 H), 3.40 (m, 2 H), 3.49 (dd, J = 10.9, 6.1 Hz, 1 H), 3.51 (dd, J = 10.9,

6.1 Hz, 1 H), 3.74 (s, 3 H), 5.40 (m, 1 H), 5.50 (m, 1 H), 6.64 (dd, J = 6.6, 2.4 Hz, 2 H),

OHHN PMP

OHHN PMP

83

6.74 (dd, J = 6.6, 2.4 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 18.0, 33.3, 55.8, 56.5,

64.4, 114.9, 116.1, 125.7, 133.8, 139.8, 152.8; HRMS, calcd for C13H19NO2: 221.1416.

Found m/z (relative intensity): 222.1449 (M++1, 4), 221.1401 (M+, 28), 191.1235 (14),

190.1195 (100).

(2R,4S)-4-methyl-2-(phenylamino)-5-hexenol (6bb)


(2R,4S)-4-methyl-2-(phenylamino)-5-hexenol (6bb): (a mixture of major and minor

isomers in a ratio of 8:1): IR (neat) 3393 (s), 3078 (m), 2926 (s), 1601 (s), 1506 (s),

1317 (s), 1030 (s), 914 (m), 748 (s), 692 (s) cm-1; 1H NMR (400 MHz, CDCl3,

major-isomer) δ 1.03 (d, J = 6.8 Hz, 3 H), 1.52 (t, J = 5.7 Hz, 2 H), 2.32 (ddm, J = 7.7,

6.8 Hz, 1 H), 3.49 (dd, J = 10.5, 5.4 Hz, 1 H), 3.55 (tdm, J = 5.4, 4.1 Hz, 2 H), 3.71 (dd,

J = 10.5, 4.1 Hz, 1 H), 4.89 (dd, J = 17.2, 0.9 Hz, 1 H), 4.92 (dd, J = 10.4, 0.9 Hz, 1 H),

5.64 (ddd, J = 17.2, 10.4, 7.7 Hz, 1 H), 6.64 (dd, J = 8.6, 1.2 Hz, 2 H), 6.70 (t, J = 7.3

Hz, 1 H), 7.15 (dd, J = 8.6, 7.3 Hz, 2 H); 13C NMR (100 MHz, CDCl3, major-isomer) δ

21.1, 35.0, 39.8, 53.5, 65.0, 113.7, 113.8, 117.8, 129.3, 143.7, 147.7; 1H NMR (400

MHz, CDCl3, minor-isomer) δ 1.00 (d, J = 6.8 Hz, 3 H), 1.50 (t, J = 5.1 Hz, 2 H), 2.32

(ddm, J = 7.7, 6.8 Hz, 1 H), 3.49 (dd, J = 10.5, 5.4 Hz, 1 H), 3.55 (tdm, J = 5.4, 4.1 Hz,

2 H), 3.71 (dd, J = 10.5, 4.1 Hz, 1 H), 4.89 (dd, J = 17.2, 0.9 Hz, 1 H), 4.92 (dd, J =

10.4, 0.9 Hz, 1 H), 5.64 (ddd, J = 17.2, 10.4, 7.7 Hz, 1 H), 6.64 (dd, J = 8.6, 1.2 Hz, 2

OHHN Ph

84

H), 6.70 (t, J = 7.3 Hz, 1 H), 7.14 (dd, J = 8.5, 7.3 Hz, 2 H); 13C NMR (100 MHz,

CDCl3, minor-isomer) δ 21.1, 35.0, 39.8, 53.5, 65.0, 113.7, 113.8, 117.8, 129.3, 143.7,

147.7; HRMS, calcd for C13H19NO: 205.1467. Found m/z (relative intensity): 206.1505

(M++1, 4), 205.1463 (M+, 20), 175.1278 (16), 174.1268 (100).

(2R,4S)-2-(4-methoxyphenylamino)-4-methyl-5-hexenol (6ba)


(2R,4S)-2-(4-methoxyphenylamino)-4-methyl-5-hexenol (6ba): IR (neat) 3383 (s),

3078 (m), 2932 (s), 1618 (s), 1418 (s), 1238 (s), 1040 (s), 914 (m), 820 (s), 667 (m)

cm-1; 1H NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.6 Hz, 3 H), 1.49 (t, J = 6.8 Hz, 2 H),

2.31 (qtm, J = 6.8, 6.6 Hz, 1 H), 3.45 (dd, J = 8.4, 3.2 Hz, 1 H), 3.46 (dd, J = 8.4, 5.5

Hz, 1 H), 3.71 (dm, J = 6.6 Hz, 1 H), 3.74 (s, 3 H), 4.89 (dd, J = 17.1, 1.2 Hz, 1 H),

4.92 (dd, J = 10.2, 1.2 Hz, 1 H), 5.63 (ddd, J = 17.1, 10.2, 8.1 Hz, 1 H), 6.64 (dd, J =

6.6, 2.2 Hz, 2 H), 6.76 (dd, J = 6.6, 2.2 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ

21.0, 34.9, 39.6, 55.0, 55.7, 64.8, 113.6, 114.8, 115.4, 141.7, 143.7, 152.3; HRMS,


235.1562 (M+, 28), 204.1378 (100).

(2R,4S)-2-(2-methoxyphenylamino)-4-methyl-5-hexenol (6bc)


OHHN PMP

85

(2R,4S)-2-(2-methoxyphenylamino)-4-methyl-5-hexenol (6bc): (a mixture of major

and minor isomers in a ratio of 8:1): IR (neat) 3414 (s), 3070 (m), 2932 (s), 2359 (s),

1601 (s), 1516 (s), 1456 (s), 1223 (s), 1030 (s), 914 (s), 737 (s) cm-1; 1H NMR (400

MHz, CDCl3, major-isomer) δ 1.03 (d, J = 6.8 Hz, 3 H), 1.54 (t, J = 6.6 Hz, 2 H), 2.31

(qm, J = 6.8 Hz, 1 H), 3.50 (dd, J = 10.4, 5.8 Hz, 1 H), 3.55 (tdm, J = 6.6, 3.9 Hz, 1 H),

3.72 (dd, J = 10.4, 3.9 Hz, 1 H), 3.85 (s, 3 H), 4.87 (dd, J = 17.8, 1.7 Hz, 1 H), 4.90 (dd,

J = 10.1, 1.7 Hz, 1 H), 5.64 (ddd, J = 17.8, 10.1, 8.0 Hz, 1 H), 6.68 (d, J = 7.6 Hz, 1 H),

6.69 (dd, J = 7.6, 1.6 Hz, 1 H), 6.77 (dd, J = 7.6, 1.2 Hz, 1 H), 6.83 (dm, J = 7.6 Hz, 1

H); 13C NMR (100 MHz, CDCl3, major-isomer) δ 21.1, 34.9, 39.8, 53.4, 55.5, 65.1,

109.8, 111.2, 113.7, 116.9, 121.3, 137.4, 143.7, 147.0; 1H NMR (400 MHz, CDCl3,

minor-isomer) δ 0.99 (d, J = 6.8 Hz, 3 H), 1.54 (t, J = 6.6 Hz, 2 H), 2.31 (qm, J = 6.8

Hz, 1 H), 3.50 (dd, J = 10.4, 5.8 Hz, 1 H), 3.55 (tdm, J = 6.6, 3.9 Hz, 1 H), 3.72 (dd, J

= 10.4, 3.9 Hz, 1 H), 3.85 (s, 3 H), 4.87 (dd, J = 17.8, 1.7 Hz, 1 H), 4.90 (dd, J = 10.1,

1.7 Hz, 1 H), 5.64 (ddd, J = 17.8, 10.1, 8.0 Hz, 1 H), 6.68 (d, J = 7.6 Hz, 1 H), 6.69 (dd,

J = 7.6, 1.6 Hz, 1 H), 6.77 (dd, J = 7.6, 1.2 Hz, 1 H), 6.83 (dm, J = 7.6 Hz, 1 H); 13C

NMR (100 MHz, CDCl3, minor-isomer) δ 21.1, 35.0, 39.8, 53.4, 55.6, 65.1, 109.8,

111.2, 113.7, 116.9, 121.3, 137.4, 143.8, 147.0; HRMS, calcd for C14H21NO2:

235.1572. Found m/z (relative intensity): 235.1568 (M+, 29), 205.1415 (19), 204.1378

(100).

OHHN OMP

86

(2R,4S)-2-(4-bromophenylamino)-4-methyl-5-hexenol (6bd)


(2R,4S)-2-(4-bromophenylamino)-4-methyl-5-hexenol (6bd): IR (neat) 3400 (s),

2927 (s), 2868 (s), 2362 (m), 2345 (s), 1593 (s), 1496 (s), 1317 (s), 1074 (s), 916 (m),

812 (s) cm-1; 1H NMR (400 MHz, CDCl3) δ 1.01 (d, J = 6.6 Hz, 3 H), 1.50 (m, 2 H),

2.02 (br, 1 H), 2.30 (m, 1 H), 3.48 (m, 2 H), 3.71 (dd, J = 13 6.2 Hz, 1 H), 4.88 (dd, J =

23, 1.2 Hz, 1 H), 4.92 (dd, J = 16, 1.2 Hz, 1 H), 5.62 (ddd, J = 17.0, 10.2, 8.1 Hz, 1 H),

6.49 (d, J = 9.0 Hz, 2 H), 7.21 (d, J = 9.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ

21.0, 34.9, 38.5, 53.4, 64.8, 109.0, 113.9, 115.0, 131.8, 143.5, 146.7; HRMS, calcd for

C13H18BrNO: 283.0572. Found m/z (relative intensity): 283.0562 (M+, 25), 254.0476

(100).

(2R,4S)-2-(4-methoxyphenylamino)-8-methyl-4-vinylnon-7-enol (6ca)


(2R,4S)-2-(4-methoxyphenylamino)-8-methyl-4-vinylnon-7-enol (6ca): IR (neat)

3368 (s), 3078 (m), 2916 (s), 1607 (m), 1514 (s), 1375 (s), 1240 (s), 1042 (s), 914 (s),

820 (s) cm-1; 1H NMR (400 MHz, CDCl3) δ 1.33 (m, 2 H), 1.46 (dd, J = 10.1, 4.4 Hz,

OHHN

Br

OHHN PMP

87

2 H), 1.56 (s, 3 H), 1.67 (s, 3 H), 1.94 (m, 2 H), 2.15 (dm, J = 4.4 Hz, 1 H), 3.44 (dd, J

= 10.0, 7.4 Hz, 1 H), 3.46 (dd, J = 10.0, 5.8 Hz, 1 H), 3.69 (m, 2 H), 3.74 (s, 3 H), 4.84

(dd, J = 17.0, 2.0 Hz, 1 H), 4.99 (dd, J = 10.2, 2.0 Hz, 1 H), 5.05 (tt, J = 5.6, 1.4 Hz, 1

H), 5.49 (ddd, J = 17.0, 10.2, 9.0 Hz, 1 H), 6.65 (dd, J = 6.6, 2.3 Hz, 2 H), 6.75 (dd, J

= 6.6, 2.3 Hz, 2 H); 13C NMR (100 MHz, CDCl3) δ 17.7, 25.6, 25.7, 35.5, 38.1, 40.5,

55.7, 65.0, 114.8, 115.5, 115.8, 124.1, 131.4, 141.2, 142.2, 152.7; HRMS, calcd for

C19H29NO2: 303.2198. Found m/z (relative intensity): 304.2201 (M+ +1, 11), 303.2183

(M+, 48), 273.2022 (19), 272.2000 (100).

3-(4-methoxyphenylamino)-6-hexene-1,2-diol (8aa)


3-(4-methoxyphenylamino)-6-hexene-1,2-diol (8aa): (a mixture of major and minor

isomers in a ratio of 3:1): IR (neat) 3356 (s), 3074 (m), 2934 (s), 1666 (s), 1441 (s),

1236 (s), 1038 (s), 822 (s) cm-1; 1H NMR (400 MHz, CDCl3, major-isomer) δ 1.62 (td,

J = 8.7, 5.9 Hz, 2 H), 2.00 – 2.33 (m, 2 H), 2.60 – 3.00 (m, 1 H), 3.35 – 3.47 (m, 1 H),

3.68 – 3.80 (m, 2 H), 3.74 (s, 3 H), 4.95 (dd, J = 9.9, 1.5 Hz, 1 H), 4.96 (dd, J = 17.8,

1.5 Hz, 1 H), 5.76 (ddt, J = 17.8, 9.9, 6.7 Hz, 1 H), 6.65 (dt, J = 9.3, 2.5 Hz, 2 H), 6.76

(dt, J = 9.3, 2.5 Hz, 2 H); 13C NMR (100 MHz, CDCl3, major-isomer) δ 30.3, 30.8,

55.7, 57.8, 64.0, 72.7, 114.9, 115.2, 115.6, 137.7, 141.1, 152.6; 1H NMR (400 MHz,

HN PMP

OHOH

88

CDCl3, minor-isomer) δ 1.62 (td, J = 8.7, 5.9 Hz, 2 H), 2.00 – 2.33 (m, 2 H), 2.60 –

3.00 (m, 1 H), 3.35 – 3.47 (m, 1 H), 3.68 – 3.80 (m, 2 H), 3.74 (s, 3 H), 4.95 (dd, J =

9.9, 1.5 Hz, 1 H), 4.96 (dd, J = 17.8, 1.5 Hz, 1 H), 5.76 (ddt, J = 17.8, 9.9, 6.7 Hz, 1 H),

6.65 (dt, J = 9.3, 2.5 Hz, 2 H), 6.76 (dt, J = 9.3, 2.5 Hz, 2 H); 13C NMR (100 MHz,



252.1614 (M++1, 4), 251.1512 (M+, 30), 220.1334 (6), 191.1258 (14), 190.1187 (100).

(E)-3-(4-methoxyphenylamino)-5-hexene-1,2-diol (8’aa)


(E)-3-(4-methoxyphenylamino)-5-hexene-1,2-diol (8’aa): (a mixture of major and

minor isomers in a ratio of 3:1): IR (neat) 3356 (s), 3074 (m), 2934 (s), 1666 (s), 1441

(s), 1236 (s), 1038 (s), 822 (s) cm-1; 1H NMR (400 MHz, CDCl3, major-isomer) δ 1.72

(d, J = 6.8 Hz, 3 H), 2.00 – 2.33 (m, 2 H), 2.60 – 3.00 (m, 1 H), 3.35 – 3.47 (m, 1 H),

3.68 – 3.80 (m, 2 H), 3.74 (s, 3 H), 5.36 – 5.43 (m, 1 H), 5.48 – 5.55, (m, 1 H), 6.65 (dt,

J = 9.3, 2.5 Hz, 2 H), 6.76 (dt, J = 9.3, 2.5 Hz, 2 H); 13C NMR (100 MHz, CDCl3,

major-isomer) δ 18.0, 33.8, 55.7, 57.4, 64.8, 72.2, 114.9, 115.2, 126.5, 128.8, 141.5,

152.8; 1H NMR (400 MHz, CDCl3, minor-isomer) δ 1.72 (d, J = 6.8 Hz, 3 H), 2.00 –

2.33 (m, 2 H), 2.60 – 3.00 (m, 1 H), 3.35 – 3.47 (m, 1 H), 3.68 – 3.80 (m, 2 H), 3.74 (s,

HN PMP

OHOH

89

3 H), 5.36 – 5.43 (m, 1 H), 5.48 – 5.55, (m, 1 H), 6.65 (dt, J = 9.3, 2.5 Hz, 2 H), 6.76

(dt, J = 9.3, 2.5 Hz, 2 H); 13C NMR (100 MHz, CDCl3, minor-isomer) δ 18.0, 33.8,

55.7, 57.4, 64.7, 72.2, 114.8, 115.2, 126.5, 128.8, 141.5, 152.8; HRMS, calcd for

C14H21NO3: 251.1521. Found m/z (relative intensity): 252.1614 (M++1, 4), 251.1512

(M+, 30), 220.1334 (6), 191.1258 (14), 190.1187 (100).

(3R,5S)-5-methyl-3-(phenylamino)-6-heptene-1,2-diol (8bb)


(3R,5S)-5-methyl-3-(phenylamino)-6-heptene-1,2-diol (8bb): (a mixture of major

and minor isomers in a ratio of 2:1): IR (neat) 3281 (s), 2961 (s), 1603 (s), 1512 (s),

1325 (s), 1024 (s), 748 (s), 692 (s) cm-1; 1H NMR (400 MHz, CDCl3, major-isomer) δ

1.01 (d, J = 6.8 Hz, 3 H), 1.54 – 1.63 (m, 2 H), 2.23 – 2.33 (qm, J = 6.8 Hz, 1 H), 3.54

– 3.77 (m, 4 H), 4.94 (dd, J = 10.3, 1.5 Hz, 1 H), 4.98 (dd, J = 17.1, 1.5 Hz, 1 H), 5.59

(ddd, J = 17.1, 10.3, 8.3 Hz, 1 H), 6.65 (td, j = 8.5, 1.0 Hz, 2 H), 6.70 – 6.74 (m, 1 H),

7.15 (dt, J = 8.5, 7.6 Hz, 2 H); 13C NMR (100 MHz, CDCl3, major-isomer) δ 21.4, 34.9,

39.0, 54.3, 64.0, 73.5, 113.7, 117.8, 118.1, 129.2, 143.4, 147.6; 1H NMR (400 MHz,

CDCl3, minor-isomer) δ 0.97 (d, J = 6.6 Hz, 3 H), 1.47 (ddd, J = 14.0, 9.8, 4.2 Hz, 2

H), 2.23 – 2.33 (qm, J = 6.8 Hz, 1 H), 3.54 – 3.77 (m, 4 H), 4.82 (dd, J = 17.3, 1.7 Hz,

1 H), 4.92 (dd, J = 9.9, 1.7 Hz, 1 H), 5.72 (ddd, J = 17.3, 9.9, 7.4 Hz, 1 H), 6.65 (td, j =

HN Ph

OHOH

90

8.5, 1.0 Hz, 2 H), 6.70 – 6.74 (m, 1 H), 7.15 (dt, J = 8.5, 7.6 Hz, 2 H); 13C NMR (100

MHz, CDCl3, minor-isomer) δ 21.2, 34.5, 38.2, 54.6, 63.8, 72.7, 113.8, 117.8, 118.0,


intensity): 236.1596 (M++1, 3), 235.1554 (M+, 12), 175.1262 (13), 174.1240 (100).

(3R,5S)-3-(4-methoxyphenylamino)-5-methyl-6-heptene-1,2-diol (8ba)


(3R,5S)-3-(4-methoxyphenylamino)-5-methyl-6-heptene-1,2-diol (8ba) : (a mixture

of major and minor isomers in a ratio of 2:1): IR (neat) 3366 (s), 3078 (m), 2932 (m),

2835 (m), 1655 (s), 1238 (s), 1036 (s), 822 (s) cm-1; 1H NMR (400 MHz, CDCl3,

major-isomer) δ 1.00 (d, J = 6.6 Hz, 3 H), 1.48 (ddd, J = 14.0, 9.7, 4.2 Hz, 1 H), 1.55

(ddd, J = 14.0, 9.7, 4.2 Hz, 1 H), 2.03 (br, 2 H) 2.25 (m, 1 H), 3.44 – 3.54 (m, 1 H),

3.74 (s, 3 H), 3.66 – 3.8 (m, 4 H), 4.80 (dd, J = 17.1, 1.3 Hz, 1 H), 4.91 (dd, J = 10.5,

1.3 Hz, 1 H), 5.57 (ddd, J = 17.1, 10.5, 8.3 Hz, 1 H), 6.68 (dd, j = 6.8, 2.3 Hz, 2 H),

6.76 (dd, J = 6.8, 2.3 Hz, 2 H); 13C NMR (100 MHz, CDCl3, major-isomer) δ 21.4,

35.0, 39.0, 55.8, 56.3, 64.1, 73.1, 114.2, 114.9, 115.9, 143.5, 143.7, 152.8; 1H NMR

(400 MHz, CDCl3, minor-isomer) δ 0.96 (d, J = 6.6 Hz, 3 H), 1.48 (ddd, J = 14.0, 9.7,

4.2 Hz, 1 H), 1.55 (ddd, J = 14.0, 9.7, 4.2 Hz, 1 H), 2.03 (br, 2 H) 2.25 (m, 1 H), 3.44 –

3.54 (m, 1 H), 3.74 (s, 3 H), 3.66 – 3.8 (m, 4 H), 4.80 (dd, J = 17.1, 1.3 Hz, 1 H), 4.97

HN PMP

OHOH

91

(dd, J = 17.4, 1.3 Hz, 1 H), 5.67 (ddd, J = 17.4, 10.2, 7.6 Hz, 1 H), 6.68 (dd, j = 6.8,

2.3 Hz, 2 H), 6.76 (dd, J = 6.8, 2.3 Hz, 2 H); 13C NMR (100 MHz, CDCl3,

minor-isomer) δ 20.4, 34.7, 39.0, 55.8, 56.3, 63.8, 73.1, 115.0, 114.9, 116.1, 143.5,


266.1678 (M++1, 3), 265.1659 (M+, 18), 205.1406 (15), 204.1406 (100).

(3R,5S)-3-(4-methoxyphenylamino)-9-methyl-5-vinyl-8-decene-1,2-diol (8ca)


(3R,5S)-3-(4-methoxyphenylamino)-9-methyl-5-vinyl-8-decene-1,2-diol (8ca): (a

mixture of major and minor isomers in a ratio of 2:1): IR (neat) 3358 (s), 3074 (s), 2916

(s), 2343 (m), 1666 (s), 1514 (s), 1238 (s), 1040 (s), 822 (s) cm-1; 1H NMR (400 MHz,

CDCl3, major-isomer) δ 1.19 – 1.38 (m, 4 H), 1.55 (s, 3 H), 1.67 (s, 3 H), 1.79 – 1.98

(dm, J = 7.5 Hz, 1 H), 2.00 – 2.17 (m, 2 H), 3.47 (dd, J = 12.0, 5.9 Hz, 1 H), 3.54 (dd, J

= 12.0, 6.9 Hz, 1 H), 3.69 – 3.80 (m, 3 H), 3.74 (s, 3 H), 4.74 (dd, J = 18.6, 2.0 Hz, 1 H),

4.94 – 5.05 (m, 1 H), 4.98 (dd, J = 10.0, 2.0 Hz, 1 H), 5.46 (ddd, J = 18.6, 10.0, 7.5 Hz,

1 H), 6.69 (d, J = 6.6 Hz, 2 H), 6.75 – 6.78 (m, 2 H); 13C NMR (100 MHz, CDCl3,

major-isomer) δ 17.7, 25.4, 25.6, 35.2, 35.4, 40.5, 55.6, 55.7, 64.0, 73.1, 114.9, 115.3,

116.2, 124.1, 124.3, 131.5, 131.6, 141.9; 1H NMR (400 MHz, CDCl3, minor-isomer) δ

1.19 – 1.38 (m, 4 H), 1.54 (s, 3 H), 1.64 (s, 3 H), 1.79 – 1.98 (dm, J = 7.5 Hz, 1 H), 2.00

HN PMP

OHOH

92

– 2.17 (m, 2 H), 3.47 (dd, J = 12.0, 5.9 Hz, 1 H), 3.54 (dd, J = 12.0, 6.9 Hz, 1 H), 3.69 –

3.80 (m, 3 H), 3.75 (s, 3 H), 4.74 (dd, J = 18.6, 2.0 Hz, 1 H), 4.94 – 5.05 (m, 1 H), 4.98

(dd, J = 10.0, 2.0 Hz, 1 H), 5.46 (ddd, J = 18.6, 10.0, 7.5 Hz, 1 H), 6.69 (d, J = 6.6 Hz, 2

H), 6.75 – 6.78 (m, 2 H); 13C NMR (100 MHz, CDCl3, minor-isomer) δ 17.7, 25.4, 25.6,

35.2, 35.4, 40.4, 55.6, 55.7, 64.0, 73.1, 114.8, 115.3, 116.3, 124.1, 124.3, 131.4, 131.6,

141.8; HRMS, calcd for C20H31NO3: 333.2304. Found m/z (relative intensity): 334.2348

(M++1, 7), 333.2312 (M+, 33), 302.2102 (4), 273.2012 (20), 272.2004 (100).

(2S, 3S, 5S)- 5-(4-methoxyphenylamino)-8-nonen-1,2,3-triol (9aa)


(2S, 3S, 5S)- 5-(4-methoxyphenylamino)-8-nonen-1,2,3-triol (9aa): (a mixture of

major and minor isomers in a ratio of 1:1): IR (neat) 3277 (m), 2932 (s), 2839 (s), 1732

(s), 1514 (s), 1456 (s), 1441 (s), 1238 (s), 1040 (s), 970 (s), 912 (m), 824 (s) cm-1; 1H

NMR (400 MHz, CDCl3, major-isomer) δ 1.43 (m, 2 H), 1.87 (dt, J = 11.5, 3.2 Hz, 2

H), 2.15- 2.30 (br d, J = 6.8 Hz, 2 H), 3.51- 3.62 (m, 4 H), 3.61 (br t, J = 3.2 Hz, 1 H),

3.74 (s, 3 H), 3.93- 4.01 (m, 1 H), 4.95 (dd, J = 11.2, 1.6 Hz, 1 H), 4.98 (dd, J = 18.1,

1.6 Hz, 1 H), 5.78 (ddd, J = 18.1, 11.2, 6.8 Hz, 1 H), 6.70 (d, J = 8.8 Hz, 2 H), 6.77 (d,

J = 8.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3, major-isomer) δ 28.7, 32.7, 36.5, 55.7,

HNPMPOH

OH

OH

93

56.8, 63.7, 71.3, 74.6, 114.5, 114.8, 118.3, 138.5, 141.1, 153.2; 1H NMR (400 MHz,

CDCl3, minor-isomer) δ 1.43 (m, 2 H), 1.87 (dt, J = 11.5, 3.2 Hz, 2 H), 2.15- 2.30 (br d,

J = 6.8 Hz, 2 H), 3.51- 3.62 (m, 4 H), 3.61 (br t, J = 3.2 Hz, 1 H), 3.74 (s, 3 H), 3.93-

4.01 (m, 1 H), 4.95 (dd, J = 11.2, 1.6 Hz, 1 H), 4.98 (dd, J = 18.1, 1.6 Hz, 1 H), 5.78

(ddd, J = 18.1, 11.2, 6.8 Hz, 1 H), 6.70 (d, J = 8.8 Hz, 2 H), 6.77 (d, J = 8.8 Hz, 2 H);


74.7, 114.6, 114.8, 118.5, 138.5, 141.1, 153.3; HRMS, calcd for C16H25NO4: 295.1783.

Found m/z (relative intensity): 296.1817 (M++1, 21), 295.1776 (M+, 100), 294.1700

(5).

(2S, 3S, 5S)- 5-(4-methoxyphenylamino)-7-nonen-1,2,3-triol (9’aa)


(2S, 3S, 5S)- 5-(4-methoxyphenylamino)-7-nonen-1,2,3-triol (9’aa): (a mixture of

major and minor isomers in a ratio of 3:1): IR (neat) 3277 (m), 2932 (s), 2839 (s), 1732

(s), 1514 (s), 1456 (s), 1441 (s), 1238 (s), 1040 (s), 970 (s), 912 (m), 824 (s) cm-1; 1H

NMR (400 MHz, CDCl3, major-isomer) δ 1.43 (m, 2 H), 1.87 (dt, J = 11.5, 3.2 Hz, 2

H), 2.15- 2.30 (m, 2 H), 2.03 (d, J = 7.3 Hz, 3 H), 3.51- 3.62 (m, 4 H), 3.61 (br t, J =

3.2 Hz, 1 H), 3.74 (s, 3 H), 3.93- 4.01 (m, 1 H), 5.32 (dq, J = 14.6, 7.3 Hz, 1 H), 5.46

(dt, J = 14.6, 6.6 Hz, 1 H), 6.70 (d, J = 8.8 Hz, 2 H), 6.77 (d, J = 8.8 Hz, 2 H); 13C

HNPMPOH

OH

OH

94

NMR (100 MHz, CDCl3, major-isomer) δ 18.0, 32.5, 37.7, 52.7, 55.7, 63.9, 71.1, 74.1,

114.9, 116.9, 125.5, 130.6, 140.8, 154.0; 1H NMR (400 MHz, CDCl3, minor-isomer) δ

1.43 (m, 2 H), 1.87 (dt, J = 11.5, 3.2 Hz, 2 H), 2.15- 2.30 (m, 2 H), 2.03 (d, J = 7.3 Hz,

3 H), 3.51- 3.62 (m, 4 H), 3.61 (br t, J = 3.2 Hz, 1 H), 3.74 (s, 3 H), 3.93- 4.01 (m, 1 H),

5.32 (dq, J = 14.6, 7.3 Hz, 1 H), 5.46 (dt, J = 14.6, 6.6 Hz, 1 H), 6.70 (d, J = 8.8 Hz, 2

H), 6.77 (d, J = 8.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3, minor-isomer) δ 18.0, 32.5,

37.4, 52.7, 55.7, 63.9, 71.1, 74.3, 114.9, 117.0, 125.2, 130.7, 140.8, 154.0; HRMS,


295.1776 (M+, 100), 294.1700 (5).

(2S, 3S, 5S, 7S)- 5-(4-methoxyphenylamino)-7-methyl-8-nonen-1,2,3-triol (9ba)


(2S, 3S, 5S, 7S)- 5-(4-methoxyphenylamino)-7-methyl-8-nonen-1,2,3-triol (9ba): (a


1639 (m), 1616 (m), 1417 (s), 1238 (s), 1180 (s), 1038 (s), 914 (s), 824 (s), 606 (s)

cm-1; 1H NMR (400 MHz, CDCl3, major-isomer) δ 1.00 (d, J = 6.6 Hz, 3 H), 1.46-

1.64 (m, 4 H), 1.88 (ddd, J = 14.4, 8.5, 3.4 Hz, 1 H), 2.26- 2.33 (br-d, J = 7.3 Hz, 1 H),

3.48- 3.80 (m, 3 H), 3.75 (s, 3 H), 3.97 (ddd, J = 11.5, 5.6, 2.9 Hz, 1 H), 4.89 (dd, J =

17.2, 1.0 Hz, 1 H), 4.91 (dd, J = 9.7, 1.7 Hz, 1 H), 5.65 (ddd, J = 17.2, 9.7, 7.3 Hz, 1

HNPMPOH

OH

OH

95

H), 6.66 (d, J = 9.0 Hz, 2 H), 6.77 (d, J = 9.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3,

major-isomer) δ 20.7, 35.1, 37.4, 42.6, 51.2, 55.8, 63.9, 71.3, 74.0, 113.5, 114.9, 116.2,


3 H), 1.46- 1.64 (m, 4 H), 1.91 (ddd, J = 14.4, 8.5, 3.4 Hz, 1 H), 2.26- 2.33 (br-d, J =

7.3 Hz, 1 H), 3.48- 3.80 (m, 3 H), 3.75 (s, 3 H), 3.97 (ddd, J = 11.5, 5.6, 2.9 Hz, 1 H),

4.89 (dd, J = 17.2, 1.0 Hz, 1 H), 4.91 (dd, J = 9.7, 1.7 Hz, 1 H), 5.65 (ddd, J = 17.2, 9.7,

7.3 Hz, 1 H), 6.67 (d, J = 10.5 Hz, 2 H), 6.69 (d, J = 10.2 Hz, 2 H); 13C NMR (100

MHz, CDCl3, minor-isomer) δ 20.7, 34.9, 37.2, 43.2, 51.6, 55.7, 63.8, 71.3, 74.2, 113.5,

114.9, 116.2, 141.0, 144.2, 153.0; HRMS, calcd for C17H27NO4: 309.1940. Found m/z

(relative intensity): 310.1951 (M++1, 19), 309.1932 (M+, 100), 248.1652 (12),

247.1566 (5).

(2S, 3S, 5S, 7S)- 5-(2-methoxyphenylamino)-7-methyl-8-nonen-1,2,3-triol (9bc)


(2S, 3S, 5S, 7S)- 5-(2-methoxyphenylamino)-7-methyl-8-nonen-1,2,3-triol (9bc): (a


2932 (s), 2360 (s), 1596 (s), 1512 (s), 1458 (s), 1227 (s), 1026 (s), 910 (s), 733 (s), 679

(s) cm-1; 1H NMR (400 MHz, CDCl3, major-isomer) δ 0.99 (d, J = 6.6 Hz, 3 H), 1.42-

1.52 (br d, J = 6.6 Hz, 4 H), 2.22- 2.27 (br d, J = 6.6 Hz, 1 H), 3.42- 3.43 (m, 1 H),

HNOMPOH

OH

OH

96

3.57- 3.58 (m, 2 H), 3.76- 3.78 (m, 3 H), 3.77 (s, 3 H), 4.01 (br, 3 H), 4.83 (d, J = 17.3

Hz, 1 H), 4.86 (d, J = 10.0 Hz, 1 H), 5.62 (ddd, J = 17.3, 10.0, 7.5 Hz, 1 H), 6.56- 6.64

(m, 1 H), 6.70- 6.72 (m, 2 H), 6.78 (t, J = 7.6 Hz, 1 H); 13C NMR (100 MHz, CDCl3,

major-isomer) δ 20.5, 34.7, 38.4, 43.3, 48.4, 55.3, 63.1, 70.1, 74.5, 109.7, 110.8, 113.1,

116.2, 121.2, 137.6, 143.9, 146.6; 1H NMR (400 MHz, CDCl3, minor-isomer) δ 0.95 (d,

J = 6.3 Hz, 3 H), 1.65- 1.78 (m, 4 H), 2.22- 2.27 (br d, J = 6.6 Hz, 1 H), 3.42- 3.43 (m,

1 H), 3.57- 3.58 (m, 2 H), 3.76- 3.78 (m, 3 H), 3.77 (s, 3 H), 4.01 (br, 3 H), 4.83 (d, J =

17.3 Hz, 1 H), 4.86 (d, J = 10.0 Hz, 1 H), 5.62 (ddd, J = 17.3, 10.0, 7.5 Hz, 1 H), 6.56-

6.64 (m, 1 H), 6.70- 6.72 (m, 2 H), 6.78 (t, J = 7.6 Hz, 1 H); 13C NMR (100 MHz,


110.8, 113.2, 116.4, 121.2, 137.5, 143.9, 146.6; HRMS, calcd for C17H27NO4:

309.1940. Found m/z (relative intensity): 309.1922 (M+, 100).

(2S, 3S, 5S, 7S)- 5-(3,4-dimethoxyphenylamino)-7-methyl-8-nonen-1,2,3-triol (9bf)


(2S, 3S, 5S, 7S)- 5-(3,4-dimethoxyphenylamino)-7-methyl-8-nonen-1,2,3-triol

(9bf): (a mixture of major and minor isomers in a ratio of 2:1):IR (neat) 3379 (s), 3078

(m), 2932 (s), 1705 (m), 1612 (s), 1458 (s), 1234 (s), 1026 (s), 918 (m), 733 (s) cm-1;

NH OH

OH

OHOMeMeO

97

1H NMR (400 MHz, CDCl3, major-isomer) δ 1.00 (d, J = 6.6 Hz, 3 H), 1.45- 1.63 (m,

4 H), 1.86 (ddd, J = 14.2, 9.3, 3.2 Hz, 1 H), 2.20- 2.40 (m, 1 H), 3.12 (br, 1 H), 3.56 (br

dd, J = 9.5, 5.4 Hz, 1 H), 3.75 (m, 2 H), 3.80 (s, 3 H), 3.82 (s, 3 H), 3.95 (ddd, J = 8.8,

5.4, 3.1 Hz, 1 H), 4.90 (d, J = 17.1 Hz, 1 H), 4.92 (d, J = 10.5 Hz, 1 H), 5.65 (ddd, J =

17.1, 10.5, 7.9 Hz, 1 H), 6.23 (dd, J = 8.5, 2.4 Hz, 1 H), 6.32 (d, J = 2.4 Hz, 1 H), 6.72

(d, J = 8.5 Hz, 1 H); 13C NMR (100 MHz, CDCl3, major-isomer) δ 20.7, 35.0, 37.7,

42.7, 50.8, 55.8, 56.6, 56.8, 63.6, 70.9, 100.5, 105.7, 113.4, 122.3, 132.3, 141.7, 144.0,

149.9; 1H NMR (400 MHz, CDCl3, minor-isomer) δ 0.96 (d, J = 6.8 Hz, 3 H), 1.45-

1.63 (m, 4 H), 1.95 (ddd, J = 14.4, 8.8, 3.2 Hz, 1 H), 2.20- 2.40 (m, 1 H), 3.12 (br, 1 H),

3.56 (br dd, J = 9.5, 5.4 Hz, 1 H), 3.75 (m, 2 H), 3.80 (s, 3 H), 3.82 (s, 3 H), 4.00 (m, 1

H), 4.88 (d, J = 18.8 Hz, 1 H), 4.98 (br d, J = 10.8 Hz, 1 H), 5.58 (ddd, J = 18.8, 10.8,

8.0 Hz, 1 H), 6.29 (dt, J = 8.5, 2.4 Hz, 1 H), 6.34 (d, J = 2.4 Hz, 1 H), 6.74 (d, J = 8.5

Hz, 1 H); 13C NMR (100 MHz, CDCl3, minor-isomer) δ 20.7, 35.0, 37.7, 42.7, 50.8,

55.8, 56.6, 56.8, 63.6, 70.9, 100.5, 105.7, 113.4, 122.3, 132.3, 141.7, 144.0, 149.9;

HRMS, calcd for C18H29NO5: 339.2046. Found m/z (relative intensity): 340 (M++1, 24),

339.2039 (M+, 100), 324 (7), 321 (3).

(2S, 3S, 5S, 7S)- 5-phenylamino-7-methyl-8-nonen-1,2,3-triol (9bb)


HN PhOH

OH

OH

98

(2S, 3S, 5S, 7S)- 5-phenylamino-7-methyl-8-nonen-1,2,3-triol (9bb): (a mixture of

major and minor isomers in a ratio of 2:1): IR (neat) 3400 (s), 2870 (s), 1639 (s), 1602

(s), 1502 (s), 1259 (s), 1180 (s), 993 (s), 873 (s), 754 (s), 667 (s) cm-1; 1H NMR (400

MHz, CDCl3, major-isomer) δ 1.01 (d, J = 6.8 Hz, 3 H), 1.52- 1.58 (m, 4 H), 1.85 (ddd,

J = 14.4, 9.3, 3.4 Hz, 2 H), 2.28- 2.35 (br d, J = 7.2 Hz, 1 H), 3.55 (br d, J = 9.3 Hz, 1

H), 3.77 (m, 3 H), 3.95 (ddd, J = 9.3, 5.4, 2.7 Hz, 1 H), 4.88 (dt, J = 17.4, 1.0 Hz, 1 H),

4.92 (dt, J = 9.9, 0.9 Hz, 1 H), 5.65 (ddd, J = 17.4, 9.9, 7.5 Hz, 1 H), 6.65 (dd, J = 8.5,

1.0 Hz, 2 H), 6.70 (dd, J = 8.5, 7.3 Hz, 1 H), 7.16 (dd, J = 8.5, 7.3 Hz, 2 H); 13C NMR

(100 MHz, CDCl3, major-isomer) δ 20.9, 35.1, 38.1, 43.1, 49.5, 63.7, 71.0, 74.1, 113.9,

114.5, 129.3, 144.0, 147.5; 1H NMR (400 MHz, CDCl3, minor-isomer) δ 0.97 (d, J =

6.8 Hz, 3 H), 1.52- 1.58 (m, 4 H), 1.85 (ddd, J = 14.4, 9.3, 3.4 Hz, 2 H), 2.28- 2.35 (br

d, J = 7.2 Hz, 1 H), 3.55 (br d, J = 9.3 Hz, 1 H), 3.77 (m, 3 H), 3.95 (ddd, J = 9.3, 5.4,

2.7 Hz, 1 H), 4.88 (dt, J = 17.4, 1.0 Hz, 1 H), 4.92 (dt, J = 9.9, 0.9 Hz, 1 H), 5.59 (br

dd, J = 9.6, 7.5 Hz, 1 H), 6.65 (dd, J = 8.5, 1.0 Hz, 2 H), 6.70 (dd, J = 7.6, 6.8 Hz, 1 H),

7.16 (dd, J = 8.5, 7.3 Hz, 2 H); 13C NMR (100 MHz, CDCl3, minor-isomer) δ 20.9,

35.0, 38.1, 43.1, 49.5, 63.7, 71.0, 74.1, 113.6, 115.5, 129.3, 144.0, 147.5; HRMS, calcd

for C16H25NO3: 279.1834. Found m/z (relative intensity): 280.1877 (M++1, 19),

279.1831 (M+, 100), 278.1753 (4), 248.1628 (6), 217.1507 (3).

(2S, 3S, 5S, 7S)- 4-(4-chlorophenylamino)-7-methyl-8-nonen-1,2,3-triol (9bg)


99

(2S, 3S, 5S, 7S)- 4-(4-chlorophenylamino)-7-methyl-8-nonen-1,2,3-triol (9bg): (a


2924 (s), 2361 (s), 1705 (s), 1597 (s), 1504 (s), 1319 (s), 1258 (s), 1180 (s), 918 (s),

818 (s), 671 (s) cm-1; 1H NMR (400 MHz, CDCl3, major-isomer) δ 0.91 (d, J = 6.6 Hz,

3 H), 1.38 (t, J = 6.6 Hz, 2 H), 1.18- 1.60 (m, 2 H), 2.18 (br quint, d, J = 6.6 Hz, 1 H),

3.34- 3.39 (m, 1 H), 3.49- 3.57 (m, 3 H), 3.70- 3.72 (m, 2 H), 3.78 (br, 3 H), 4.76 (d, J

= 17.2 Hz, 1 H), 4.83 (d, J = 10.2 Hz, 1 H), 5.52 (ddd, J = 17.2, 10.2, 7.9 Hz, 1 H),

6.46 (d, J = 8.8 Hz, 2 H), 6.97 (d, J = 8.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3,

major-isomer) δ 20.0, 34.9, 38.4, 43.1, 49.2, 63.1, 70.2, 74.5, 113.6, 114.5, 121.6,


3 H), 1.38 (t, J = 6.6 Hz, 2 H), 1.18- 1.60 (m, 2 H), 2.18 (br quint, d, J = 6.6 Hz, 1 H),

3.34- 3.39 (m, 1 H), 3.49- 3.57 (m, 3 H), 3.70- 3.72 (m, 2 H), 3.78 (br, 3 H), 4.76 (d, J

= 17.2 Hz, 1 H), 4.83 (d, J = 10.2 Hz, 1 H), 5.52 (ddd, J = 17.2, 10.2, 7.9 Hz, 1 H),

6.51 (d, J = 8.8 Hz, 2 H), 7.02 (d, J = 8.8 Hz, 2 H); 13C NMR (100 MHz, CDCl3,

minor-isomer) δ 21.0, 34.8, 38.4, 42.7, 49.2, 63.1, 70.2, 74.4, 113.7, 114.5, 121.6,

129.1, 143.8, 146.5; HRMS, calcd for C16H24ClNO3: 313.1445. Found m/z (relative

intensity): 314.1446 (M++1, 6), 313.1418 (M+, 29), 245.0748 (13), 244.0726 (100).

NH OH

OH

OH

Cl

100

(2S, 3S, 5S, 7S)- 5-(4-methoxyphenylamino)-7-vinyl-11-dodecen-1,2,3-triol (9ca)


(2S, 3S, 5S, 7S)- 5-(4-methoxyphenylamino)-7-vinyl-11-dodecen-1,2,3-triol (9ca):

(a mixture of major and minor isomers in a ratio of 1:1): IR (neat) 3300 (m), 2912 (s),

2835 (s), 1639 (s), 1618 (s), 1500 (s), 1456 (s), 1294 (s), 1238 (s), 1180 (s), 1039 (s),

916 (s), 821 (s), 748 (s) cm-1; 1H NMR (400 MHz, CDCl3, major-isomer) δ 1.18- 1.36

(m, 2 H), 1.46- 1.71 (m, 2 H), 1.56 (s, 3 H), 1.67 (s, 3 H), 1.82- 2.00 (m, 2 H), 1.91

(ddd, J = 14.1, 9.2, 3.7 Hz, 2 H), 2.04- 2.16 (m, 1 H), 3.53- 3.59 (br dd, J = 9.2, 5.3 Hz,

1 H), 3.62- 3.65 (br d, J = 3.7 Hz, 1 H), 3.71- 3.85 (m, 2 H), 3.75 (s, 3 H), 3.95- 4.00

(m, 1 H), 4.86 (dd, J = 17.1, 1.7 Hz, 1 H), 4.99 (dd, J = 10.1, 1.7 Hz, 1 H), 5.02- 5.06 (t

m, J = 7.1 Hz, 1 H), 5.49 (ddd, J = 17.1, 10.1, 7.1 Hz, 1 H), 6.67 (d, J = 8.9 Hz, 2 H),

6.76 (d, J = 8.9 Hz, 2 H); 13C NMR (100 MHz, CDCl3, major-isomer) δ 17.8, 25.6,

25.8, 35.4, 37.6, 40.7, 41.1, 51.6, 55.8, 63.8, 71.4, 74.1, 114.9, 115.5, 116.5, 124.2,

131.5, 142.6, 142.8, 153.2; 1H NMR (400 MHz, CDCl3, minor-isomer) δ 1.18- 1.36 (m,

2 H), 1.46- 1.71 (m, 2 H), 1.56 (s, 3 H), 1.67 (s, 3 H), 1.82- 2.00 (m, 2 H), 1.91 (ddd, J

= 14.1, 9.2, 3.7 Hz, 2 H), 2.04- 2.16 (m, 1 H), 3.53- 3.59 (br dd, J = 9.2, 5.3 Hz, 1 H),

3.62- 3.65 (br d, J = 3.7 Hz, 1 H), 3.71- 3.85 (m, 2 H), 3.75 (s, 3 H), 3.95- 4.00 (m, 1

H), 4.80 (dd, J = 17.6, 1.6 Hz, 1 H), 4.97 (dd, J = 10.2, 1.6 Hz, 1 H), 5.02- 5.06 (t m, J

HN R1OH

OH

OH

101

= 7.1 Hz, 1 H), 5.49 (ddd, J = 17.1, 10.1, 7.1 Hz, 1 H), 6.67 (d, J = 8.9 Hz, 2 H), 6.78

(d, J = 9.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3, minor-isomer) δ 17.8, 25.4, 25.7,

35.4, 37.6, 40.7, 41.1, 51.6, 55.7, 63.8, 71.4, 74.2, 114.8, 115.5, 116.5, 124.2, 131.5,


intensity): 377.2561 (M+, 100).

General procedure 2: for the Nickel-catalyzed homoallylation of N,O-acetals

prepared from carbohydrate and primary amines with dienes (entry 8, Table 4)




charged. A solution of D-ribose (150 mg, 1 mmol) and p-anisidine (246 mg, 2 mmol)

in dry DMF (5 mL) was refluxed for 120 min under nitrogen. The solvent was

removed by distillation under reduced pressure (azeotropic removal of water). A

mixture of Ni(cod)2 (27.5 mg, 0.1 mmol) and isoprene (800 µL, 8 mmol) dissolved in

THF (2 mL) and triethylborane (6.0 mmol, 1.0 M THF solution) were successively

added to the N,O-acetal solution via the dropping funnel over a period of 10 min. The

reaction mixture was stirred at 50 ˚C for 48 h and monitored by TLC. After the



washed with 2 M HCl, with sat. NaHCO3, and brine. The aqueous layer was

102

extracted with 30 mL of EtOAc. The combined organic phases were dried (MgSO4)

and concentrated in vacuo, and the residual oil was subjected to column

chromatography over silica gel (eluent; hexane/EtOAc = 0/100 v/v) to afford 10ba

(192 mg, 57%; Rf = 0.30; hexane/EtOAc = 0/100 v/v) in a 2:1 ratio.

5-[(4-Methoxyphenyl)amino]-7-methylnon-8-ene-1,2,3,4-tetraol (10ba)


5-[(4-Methoxyphenyl)amino]-7-methylnon-8-ene-1,2,3,4-tetraol (10ba): (a mixture

of major and minor isomers in a ratio of 2:1): IR (neat) 3400 (m), 2930 (m), 1653 (s),

1539 (s), 1456 (s), 1231 (s), 1180 (s), 1038 (s), 916 (s), 829 (s), 735 (s), 667 (s) cm-1;

1H NMR (400 MHz, CDCl3, major-isomer) δ 0.98 (d, J = 6.6 Hz, 3 H), 1.48- 1.57 (br d,

J = 13.8 Hz, 2 H), 1.74 (ddd, J = 13.8, 10.4, 2.9 Hz, 1 H), 2.27- 2.29 (br d, J = 7.7 Hz,

1 H), 3.61- 3.69 (m, 2 H), 3.74 (s, 3 H), 3.76- 3.90 (m, 3 H), 4.82 (d, J = 17.1 Hz, 1 H),

4.92 (dd, J = 10.2, 1.7 Hz, 1 H), 5.60 (ddd, J = 17.1, 10.2, 7.7 Hz, 1 H), 6.78 (d, J =

10.6 Hz, 2 H), 6.79 (d, J = 10.6 Hz, 2 H); 13C NMR (100 MHz, CDCl3, major-isomer)

δ 21.7, 35.2, 37.0, 55.9, 57.5, 63.6, 73.0, 73.4, 73.9, 114.4, 115.0, 117.4, 143.9, 153.9,

162.5; 1H NMR (400 MHz, CDCl3, minor-isomer) δ 0.96 (d, J = 6.8 Hz, 3 H), 1.48-

1.57 (br d, J = 13.8 Hz, 2 H), 1.74 (ddd, J = 13.8, 10.4, 2.9 Hz, 1 H), 2.27- 2.29 (br d, J

= 7.7 Hz, 1 H), 3.61- 3.69 (m, 2 H), 3.75 (s, 3 H), 3.76- 3.90 (m, 3 H), 4.82 (d, J = 17.1

HNPMP

OH

OH

OH

OH

103

Hz, 1 H), 4.91 (d, J = 11.2 Hz, 1 H), 5.60 (ddd, J = 17.1, 10.2, 7.7 Hz, 1 H), 6.78 (d, J

= 10.6 Hz, 2 H), 6.79 (d, J = 10.6 Hz, 2 H); 13C NMR (100 MHz, CDCl3,

minor-isomer) δ 21.7, 34.9, 36.6, 55.9, 57.5, 63.6, 73.2, 73.7, 73.9, 114.4, 115.1, 117.8,


intensity): 326.1940 (M++1, 20), 325.1873 (M+, 100).

(2R, 3S, 4R, 6S, 8S)-6-(4-methoxyphenylamino)-8-methyl-9-decen-1,2,3,4-tetraol

(11ba)


(2R, 3S, 4R, 6S, 8S)-6-(4-methoxyphenylamino)-8-methyl-9-decen-1,2,3,4-tetraol

(11ba): (a mixture of major and minor isomers in a ratio of 1:1): IR (KBr) 3285 (s),

2937 (m), 2924 (m), 1514 (s), 1412 (m), 1240 (s), 1074 (s), 1040 (s), 822 (w), 640 (w)

cm-1; 1H NMR (400 MHz, CDCl3, major-isomer) δ 1.00 (d, J = 6.8 Hz, 3 H), 1.44- 1.62

(m, 4 H), 2.04- 2.11 (ddd, J = 5.1, 9.3, 12.7, 1 H), 2.26 (br d, J = 7.5 Hz, 1 H), 3.51-

3.83 (m, 5 H), 3.74 (s, 3 H), 4.16- 4.20 (m, 1 H), 4.89 (d, J = 18.0 Hz, 1 H), 4.92 (d, J =

10.5 Hz, 1 H), 5.63 (ddd, J = 17.1, 10.2, 7.8 Hz, 1 H), 6.73 (d, J = 9.0 Hz, 2 H), 6.77 (d,

J = 9.0 Hz, 2 H); 13C NMR (100 MHz, CDCl3, major-isomer) δ 20.8, 35.2, 37.9, 42.5,

51.7, 55.9, 64.0, 68.9, 72.9, 74.7, 113.7, 115.0, 116.7, 140.8, 144.1, 153.3; 1H NMR

(400 MHz, CDCl3, minor-isomer) δ 0.93 (d, J = 6.8 Hz, 3 H), 1.44- 1.62 (m, 4 H), 2.04-

2.11 (ddd, J = 5.1, 9.3, 12.7, 1 H), 2.26 (br d, J = 7.5 Hz, 1 H), 3.51- 3.83 (m, 5 H), 3.76

HNPMPOH

OH

OH

OH

104

(s, 3 H), 4.16- 4.20 (m, 1 H), 4.88 (d, J = 17.3 Hz, 1 H), 4.97 (d, J = 9.3 Hz, 1 H), 5.63

(ddd, J = 17.1, 10.2, 7.8 Hz, 1 H), 6.72 (d, J = 10.7 Hz, 2 H), 6.79 (d, J = 9.0 Hz, 2 H);


68.9, 73.0, 74.3, 113.5, 115.0, 116.7, 140.8, 144.3, 153.3; HRMS, calcd for C18H29NO5:

339.2046. Found m/z (relative intensity): 340.2072 (M++1, 20), 339.2037 (M+, 100).

105

References

(1) Tamaru, Y. Modern Organonickel Chemistry; Wiley-VCH: Weinheim, 2005.

(2) Behr, A.; Neubert, P. Piperylene - A versatile basic chemical in catalysis. Chem

Cat Chem 2014, 6, 412-428.

(3) (a) Bertelo, C.; Schwartz, J. Hydrozirconation V. g,d-Unsaturated aldehydes and

halides from 1,3-dienes via organozirconium(IV) intermediates. J. Am. Chem.

Soc. 1976, 98, 262-264.

(b) Yasuda, H.; Tatsumi, K.; Nakamura, A. Unique chemical behavior and

bonding of early-transition-metal-diene complexes. Acc. Chem. Res. 1985, 18,

120-126.

(4) (a) Kimura, M.; Ezoe, A.; Shibata, K.; Tamaru, Y. Novel and highly regio- and

stereoselective nickel-catalyzed homoallylation of benzaldehyde with 1,3-dienes.

J. Am. Chem. Soc. 1998, 120, 4033-4034.

(b) Kimura, M.; Ezoe, A.; Mori, M.; Iwata, K.; Tamaru, Y. Regio- and

stereoselective nickel-catalyzed homoallylation of aldehydes with 1,3-dienes. J.

Am. Chem. Soc. 2006, 128, 8559-8568.

106

(5) Kimura, M.; Fujimatsu, H.; Ezoe, A.; Shibata, K.; Shimizu, M.; Matsumoto, S.;

Tamaru, Y. Nickel-catalyzed homoallylation of aldehydes and ketones with

1,3-dienes and complementary promotion by diethylzinc or triethylborane.

Angew. Chem. Int. Ed. 1999, 38, 397-400.

(6) Kimura, M.; Ezoe, A.; Tanaka, S.; Tamaru, Y. Nickel-catalyzed homoallylation

of aldehydes in the presence of water and alcohols. Angew. Chem. Int. Ed. 2001,

40, 3600-3602.

(7) Kimura, M.; Miyachi, A.; Kojima, K.; Tanaka, S.; Tamaru, Y. Highly stereo- and

regioselective Ni-catalyzed homoallylation of aldimines with conjugated dienes

promoted by diethylzinc. J. Am. Chem. Soc. 2004, 126, 14360-14361.

(8) (a) Kim, H.-J.; Ricardo, A.; Illangkoon, H.-I.; Kim, M. J.; Carrigan, M. A.; Frye,

F.; Benner. S. A. Synthesis of carbohydrates in mineral-guided prebiotic cycles.

J. Am. Chem. Soc. 2011, 133, 9457-9468.

(b) Archer, R.M.; Royer, S. F.; Mahy, W.; Winn, C.L.; Danson, M.J.; Bull, S. D.

Syntheses of 2-keto-3-deoxy-D-xylonate and 2-keto-3-deoxy-L-arabinonate as

stereochemical probes for demonstrating the metabolic promiscuity of sulfolobus

solfataricus towards D-xylose and L-arabinose. Chem. Eur. J. 2013, 19,

2895-2902.

107

(9) Li, Z.; Cai, L.; Wei, M.; Wang, P. G. One-pot four-enzyme synthesis of ketones

with fructose 1,6-bisphosphate aldolases from staphylococcus carnosus and rabit

muscle. Carbohydrate Res. 2012, 357, 143-146.

(10) (a) Kodato, S.; Nakagawa, M.; Nakayama, K.; Hino, T. Synthesis of cerebroside

B1b with antiulcerogenic activity I. Synthesis of ceramides with optically active

α-hydroxypalmitic acids. Tetrahedron 1989, 45, 7247-7262.

(b) Mukai, R.; Horino, Y.; Tanaka, S.; Tamaru, Y.; Kimura, M. Pd(0)-catalyzed

amphiphilic activation of bis-allyl alcohol and ether. J. Am. Chem. Soc. 2004,

126, 11138-11139.

(c) Kimura, M.; Shimizu, M.; Tanaka, S.; Tamaru, Y. Pd-catalyzed nucleophilic

allylic alkylation of aliphatic aldehydes by the use of allyl alcohols.

Tetrahedron 2005, 61, 3709-3718.

(d) Yamaguchi, Y.; Hasimoto, M.; Tohyama, K.; Kimura, M. Nucleophilic

allylation of N,O-acetals with allylic alcohols promoted by Pd/Et3B and Pd/Et2Zn

systems, Tetrahedron Lett. 2011, 52, 913-915.

109

Chapter 3

Multicomponent Coupling Reaction via Nickelacycle:

Efficient and Selective Formation of Unsaturated Carboxylic Acids and

Phenylacetic Acids from Diketene

Summary: Ni-catalyzed multicomponent coupling reaction of alkyne, dimethylzinc,

and diketene (as butenoic acid equivalent) to provide 3-methylene-4-hexenoic acids in a

single manipulation is described. Under similar catalytic conditions, Et2Al(OEt)

accelerates a formal [2+2+2] cycloaddition reaction with diketene and two equivalents

of alkynes to produce phenylacetic acid derivatives. Furthermore, in the presence of

ligand, such as PPh3, symmetrical substituted phenylacetic acids are produced with

accompanying cleavage reaction of the C–C double bond of diketene via

nickelacyclopentane rearrangement.

+

R1

R2

cat. Ni(0)

Me2Zn R1 •OH

O•Me

R2

cat. Ni(0)

Et2Al(OEt)•

•

OH

O

R1

R2

R1

R2

!

•

•

OO

!

+

R1

R2

cat. Ni/PPh3

Me2Al(OMe) R1 •OH

OMe•

R2

cat. Ni/PPh3

Et2Al(OEt)•

•OH

O

R1

R2

•

•

OO

!

R2

R1

110

Introduction

Diketene is a unique and important key intermediate formed by dimerization of

ketene1, and is often used as an acetoacetylation reagent for versatile nucleophiles,

such as alcohols, amines, thiols and carbanions, in organic synthesis (Scheme 1, path

a)2. In the presence of transition metal catalysts, diketene smoothly reacts with

organometallic compounds, such as Grignard reagents and organozinc reagents, to

cleave the vinyl-oxygen bond to construct 3-substituted 3-butenoic acids (Scheme 1,

path b)3. The 3-butenoic acid skeleton serves as a synthon for the preparation of

physiologically active molecules and the fine chemicals4.

Scheme 1. Reactivity of Diketene with Nucleophiles

Phenylacetic acid (α-toluic acid) acts as an active auxin and is a critical

constituent of many physiologically active molecules, such as tetraline-based natural

products, analgesics, and non-steroidal anti-inflammatory drugs (NSAIDs)5.

Although efficient preparations of phenylacetic acid and its analogues are widely

metalcatalyst

RMgBr

path b

OO

!

!

b

aR CO2HNu

OO

Nucleophile

path a

111

demanded for use in medicinal chemistry, most involve some limitations of handling

and harsh reaction conditions6. Therefore, straightforward and selective formations

of unsaturated carboxylic acids and phenylacetic acids from commercially available

diketene promoted by transition metal catalysts with organometallic reagents will be

beneficial.

Nickel-catalyzed coupling reactions are an attractive synthetic method for the

construction of useful and complicated molecules in modern organic chemistry7. We

have previously demonstrated the Ni(0)-catalyzed multicomponent coupling reaction

of alkyne, dimethylzinc, and unsaturated hydrocarbons (such as conjugated dienes and

vinylcyclopropanes) to accomplish C–C bond formations with high regio- and

stereoselectivities8. All of these coupling reactions proceeded via nickelacyle

intermediates by oxidative cyclization of unsaturated hydrocarbons and Ni(0) catalyst.

Herein, we would like to disclose the Ni-catalyzed multicomponent coupling

reaction of alkyne, dimethylzinc, and diketene (as butenoic acid equivalent) to provide

3-methylene-4-hexenoic acids in a single manipulation (Scheme 2). Under similar

catalytic conditions, Et2Al(OEt) accelerates a formal [2+2+2] cycloaddition reaction

with diketene and two equivalents of alkynes to produce phenylacetic acid derivatives.

Furthermore, in the presence of ligand, symmetrically substituted phenylacetic acids

are produced with accompanying cleavage of the C–C double bond of diketene.

Although Ni-catalyzed cycloaddition reactions with alkynes have been well developed9,

112

efficient syntheses of phenylacetic acids via cycloaddition reaction with alkyne and

diketene have not been reported to date.

Scheme 2. Ni-Catalyzed Multicomponent Coupling Reaction of Diketene with

Organometals

Ni-catalyst

Me2Zn+ R OH

O

R

Me

•

•

OH

O

RR

RR

OO

•

•OH

O

RR

RR

R R

no ligand ligand

Ni-catalyst

Et2Al(OEt)

113


The three-component coupling reaction with alkyne, diketene, and dimethylzinc

was conducted in the presence of Ni(acac)2 catalyst (1 mol%) in THF under nitrogen

atmosphere. Table 1 summarizes the results obtained from using a wide variety of

alkynes, including symmetrical and unsymmetrical substituted alkynes. Symmetrical

substituted alkynes, such as 2-butyne, 3-hexyne, and 4-octyne reacted with diketene and

dimethylzinc smoothly to give the three-component coupling products 3 in excellent

yields as a single isomer (entries 1-3, Table 1).

Bis(trimethylsilyl)acetylene also participated in a similar coupling reaction to

afford 3d in reasonable yield (entry 4, Table 1). Diphenylacetylene provided the

expected coupling product 3e in modest yield (entry 5, Table 1). An electron-

deficient alkyne such as dimethyl acetylenedicarboxylate did not take part in the

reaction. The regioselectivity of the unsymmetrical alkynes depended on the type of

substituents. 1-Trimethylsilyl-1-propyne coupled with dimethylzinc at the trimethyl-

silyl-substituted carbon atom and diketene at the methyl-substituted carbon atom to

provide 3f in syn addition manner as a single stereoisomer (entry 6, Table 1).

1-Trimethylsilyl-2-phenylethyne and 1-phenyl-1-butyne provided the expected

unsaturated carboxylic acids as a mixture of regioisomers of 3g and 3h, respectively

(entries 7 and 8, Table 1).

114

Table 1. Scope of the Nickel-Catalyzed Three-Component Coupling Reaction of Diketene, Alkyne 2, and Me2Zna

entry alkyne R1 R2 time (h) yield of 3 (%) [ratio]

1 Me Me (2a) 1 3a: 91

2 Et Et (2b) 3 3b: 95

3 n-Pr n-Pr (2c) 3 3c: 90

4 TMS TMS (2d) 6 3d: 81

5 Ph Ph (2e) 24 3e: 29

6 TMS Me (2f) 3 3f: 91 [single]

7 TMS Ph (2g) 24 3g: 87 [3:1]b

8 Ph Et (2h) 24 3h: 87 [10:1]c

a The reaction was undertaken in the presence of Ni(acac)2 (0.01 mmol), alkyne (1 mmol), diketene (1.5 mmol), and Me2Zn (1.2 mmol) in THF at 50 ˚C under nitrogen atmosphere. Yields were calculated based on alkyne. b The ratio shows the regioisomeric ratio with respect to olefin geometry. Major isomer is depicted as the structure of compound 3. c The substituents of R1 and R2 on major isomer are opposite each other on minor isomer.

Ni(acac)2

Me2Zn+ R1 OH

O

R2

Me

OO

R1 R2H+

1 2 3

115

A plausible mechanism for the coupling reaction with alkyne, diketene, and

dimethylzinc is illustrated in Scheme 3. Ni-catalyzed oxidative cyclization of alkyne

and diketene in the presence of dimethylzinc proceeds to form nickelacyclopentene

intermediate I, which is followed by C–O bond cleavage to provide 7-membered oxa-

nickelacycles II. The methyl group transfer from dimethylzinc to Ni metal provides

unsaturated carboxylic acids 3 via reductive elimination and regeneration of the active

Ni(0) catalyst.

Scheme 3. Plausible Reaction Mechanism for Ni-Catalyzed Multicomponent

Coupling Reaction of Diketene and Alkyne with Me2Zn

R1 OH

O

R2

Me

3

OO

-Ni(0)

R1

R2

NiO

O

Ni

R2

R1

ZnMe2

NiO

R2

R1

OZnMe2

NiO

R2

R1

O

NiO

R2

R1

OH+

Me2Zn

ZnMeMe

ZnMe

Me

I II

116

The features of the coupling reaction with diketene and alkyne promoted by Ni

catalyst changed dramatically when organoaluminum reagents were used in place of

dimethylzinc (Table 2). For example, in the presence of Ni(cod)2 catalyst in THF

solvent, Me3Al, diketene, and 3-hexyne combined in a 1:1:1 ratio to form the

three-component coupling product 3b as well as the products shown in Table 1 (entry 1,

Table 2). Under similar conditions, complex mixtures were produced using Et3Al,

Et2AlCl, and Et2Al(OEt) (entries 2-4, Table 2). Among these investigations using

various kinds of solvents, toluene was most effective for the cycloaddition reaction,

providing ethyl-substituted phenylacetic acids.

In the presence of Ni catalyst and Me3Al, diketene underwent [2+2+2] cyclo-

addition with two equivalents of 3-hexyne to afford phenylacetic acid 5b in 34% yield,

along with the linear coupling product, trienyl carboxylic acid 4ba, in 24% yield as a

byproduct (entry 5, Table 2). Use of Et3Al also produced a similar result to give a

mixture of 4bb and 5b in modest yields (entry 6, Table 2). Although Et2AlCl resulted

in the formation of a complex mixture, Et2Al(OEt) effectively promoted the [2+2+2]

cycloaddition reaction to provide 5b in 98% as a single product (entries 7-8, Table 2).

117


of Diketene, Alkyne 2b, and Organoaluminuma

entry organoaluminum solvent yield of 3b, 4 and 5b (%)

1 Me3Al THF 3b: 50

2 Et3Al THF complex mixture

3 Et2AlCl THF complex mixture

4 Et2Al(OEt) THF complex mixture

5 Me3Al toluene 4ba: 24(R = Me), 5b: 34

6 Et3Al toluene 4bb: 34(R = Et), 5b: 10

7 Et2AlCl toluene complex mixture

8 Et2Al(OEt) toluene 5b: 98

a The reaction was undertaken in the presence of Ni(cod)2 (0.1 mmol), alkyne (1 mmol), diketene (3 mmol), and organoaluminum (1.2 mmol) at r.t. under nitrogen atmosphere for 72 h.

Et OH

O

Et

EtEt

R

OH

O

EtEt

EtEt

Ni-catalyst

organoaluminum+

Et OH

O

Et

Me

OO

Et EtH+

1 2b

3b 4 5b

118

As shown in Table 3, the cycloaddition reaction of diketene with alkynes in the

presence of Ni catalyst and Et2Al(OEt) was applied to a wide variety of alkynes.

Surprisingly, use of phosphine ligands under similar catalytic conditions changed the

outcome to provide the regioisomeric phenylacetic acid 6 exclusively. Among the

results of utilizing monodentate and bidentate phosphine ligands, PPh3 was the most

efficient ligand to furnish phenylacetic acids 6 as the sole products (entries 9-12, Table

3). Symmetrical dialkyl-substituted alkynes underwent the cycloaddition reaction with

diketene to provide unsymmetrical phenylacetic acids 5 by means of the Ni catalyst and

Et2Al(OEt) system in the absence of PPh3 (entries 1-4, Table 3), diphenylacetylene

provided the expected coupling product 5e in modest yield (entry 5, Table 3), whereas

the formal [2+2+1+1] cycloaddition reaction product, symmetrically substituted

phenylacetic acids 6, were selectively produced in the presence of PPh3 ligand (entries 9,

and 13-16, Table 3). The structures of both the unsymmetrical and symmetrical

phenylacetic acids 5b and 6b were determined unequivocally by X-ray crystallographic

analysis, as shown in Figure 1 and 210. Although cycloaddition reactions involving

unsymmetrical disubstituted alkynes often exhibit complicated regioselectivities11, the

desired coupling products 5f and 6f were produced as a single isomer in the case of

using of 1-trimethylsilyl-1-propyn regardless of the presence or absence of phosphine

ligand (entries 6 and 17, Table 3). Terminal alkynes possessing t-Bu and TMS groups

could participate in the coupling reaction and the distinctive regioselective formations

of phenylacetic acids 5 and 6 were accomplished (entries 7 and 8, 18 and 19, Table 3).

119

Figure 1. ORTEP drawing of 5b with 50% probability ellipsoids.

120

Figure 2. ORTEP drawing of 6b with 50% probability ellipsoids.

121

The cycloaddition reaction was applied to the construction of a benzobicyclic ring

via coupling reaction of a diyne moiety with diketene. 3,9-Dodecadiyne underwent

the cycloaddition reaction with diketene and provided tetrahydronaphthylacetic acid 5i

using the Ni-catalyst and Et2Al(OEt) system (eq 1). Unfortunately, in the presence of

PPh3, an intractable mixture was obtained from 3,9-dodecadiyne under similar reaction

condition.

Et

EtOH

ONi(cod)2

(0.05 mmol)

Et2Al(OEt)(1.2 mmol)

toluene (5 mL)r.t., 72 h

+O

O

H+

1 : 1.5 mmol 2i : 0.5 mmol 5i (51%)

Et

Et(1)

122

Table 3. Scope of the Nickel-Catalyzed Three-Component Coupling Reaction of Diketene, Alkyne 2, and Organoaluminuma

entry alkyne R1 R2 ligand yield of 5 and 6 (%)

1 Me Me (2a) none 5a: 80

2 Et Et (2b) none 5b: 98

3 n-Pr n-Pr (2c) none 5c: 76

4 n-Bu n-Bu (2j) none 5j: 65

5 Ph Ph (2e) none 5e: 24

6 TMS Me (2f) none 5f: 77b

7 t-Bu H (2k) none 5k: 65

8 TMS H (2l) none 5l: 40

9 Et Et (2b) PPh3 6b: 73

10 Et Et (2b) P(c-Hex)3 6b: 20

11 Et Et (2b) P(n-Bu)3 complex mixture

cat. Ni(cod)2

Et2Al(OEt)+

OO

R1 R2H+

1 2b

•

•

OH

O

R1

R2

R1

R2

•

•OH

O

R1

R2

R2

R1

5 6

123


12 Et Et (2b) Xantphos 6b: 22

13 Me Me (2a) PPh3 6a: 60

14 n-Pr n-Pr (2c) PPh3 6c: 80

15 n-Bu n-Bu (2j) PPh3 6j: 71

16 Ph Ph (2e) PPh3 6e: 50

17 TMS Me (2f) PPh3 6f: 45

18 t-Bu H (2k) PPh3 6k: 34

19 TMS H (2l) PPh3 6l: 60

a The reaction was undertaken in the presence of Ni(cod)2 (0.1 mmol), ligand (0.2 mmol), alkyne (1 mmol), diketene (3 mmol), and Et2Al(OEt) (1.2 mmol) in toluene (5 mL) at r.t. under nitrogen atmosphere for 72 h. b In entry 6, 5f was obtained as a desilylation product 5f’ (R1 = H) in 77%.

The reactions of stoichiometric amount of Ni(cod)2, alkyne, and diketene without

Et2Al(OEt) were conducted (Scheme 4). In the absence of phosphine ligand, a

mixture of Ni(cod)2 (0.5 mmol), 3-hexyne (1 mmol), and diketene (0.5 mmol) did not

provide the expected phenylacetic acid 5b, and instead the intractable mixture was

obtained. On the other hand, in the presence of two equivalents of PPh3 based on

Ni(0) complex, the reaction mixture of Ni(cod)2 (0.5 mmol), PPh3 (1.0 mmol),

3-hexyne (1 mmol), and diketene (0.5 mmol) stirring for 72 hours followed by

124

hydrolysis with acidic water provided the symmetrical phenylacetic acid 6b in 54% as

a sole product. At the initial stage of the reaction for 1 hour,

(3E)-4-ethyl-5-methylene-3-heptenoic acid 7b was obtained in 80% with high

stereoselectivity. Furthermore, we would like to argue the cross-coupling reaction of

a mixture of stoichiometric amount of diketene, alkyne, PPh3, and Ni(cod)2 complex

with phenylmagnesium bromide. Addition of PhMgBr solution to the mixture of

Ni(cod)2 (0.5 mmol), PPh3 (1 mmol), 3-hexyne (0.5 mmol), and diketene (0.5 mmol)

provided (3Z)-4-ethyl-5-methylene-3-phenyl-3-heptenoic acid 8b in 26%, along with

(3Z)-4-ethyl-5-methylene-3-[(3Z)-4-phenyl-3-hexenyl]-3-heptenoic acid 9b in 39% (eq

2). These results suggest the cleavage reaction of C–C double bond of diketene

proceeds via a crucial key intermediate by the synergistic effect of Ni active species

and PPh3 ligand.

125

Scheme 4. C–C Bond Cleavage Reaction of Diketene Promoted by Stoichiometric Amount of Ni(0) in the Presence or in the Absence of Phosphine Ligand

Et OH

OH

Et

+O

O

1 : 0.5 mmol 2b : 1 mmol

Et

Et

+ Ni(cod)2

0.5 mmol

PPh3

toluene (5 mL)r.t.

H+

OH

O

EtEt

EtEt

OH

O

Et

EtEt

Et

5b 6b 7b

PPh3 (mmol) time (h) Product

0 72 complex mixture

1 72 6b (54%)

1 1 7b (80%)

Et OH

OPh

EtEt OH

O

Et

EtPhEt

+O

O1 : 0.5 mmol 2b :0.5 mmol

Et

Et

+ Ni(cod)2

0.5 mmol

PPh3(1 mmol)

toluene (5 mL)r.t., 24 h

PhMgBr(0.6 mmol)

overnight

H+

r.t., 24 h

(2)

8b: 26% 9b: 39%

126

Although it is premature to provide a complete explanation of the reactivities

described here, a plausible mechanism for the cycloaddition reactions of diketene and

alkyne promoted by Ni catalyst and Et2AlX are proposed in Scheme 5 and 6. In the

absence of phosphine ligand, oxidative cyclization of alkyne and diketene with Ni(0)

catalyst provides nickelacycle I, which undergoes the ring expansion reaction to form

oxanickelacycle intermediate II (Scheme 5). Further insertion of an additional alkyne

promoted by Et2AlX to afford vinylnickel intermediate III via transmetalation with

Et2AlX. Intramolecular carbonickelation via 6-endo cyclization of III (X = OEt), and

the subsequent β-hydride elimination occurs to afford phenylacetic acid salt 5 with

liberation of Ni(0) species12. For Me3Al and Et3Al, reductive elimination might

proceed through the intermediate III (X = Me or Et) rather than carbonickelation to

afford the linear unsaturated carboxylic acids 4ba and 4bb as a major product13.

127

Scheme 5. Plausible Reaction Mechanism for the Formation of Phenylacetic

Acids in the Absence of PPh3

The similar catalytic system, in the presence of PPh3 ligand, might promote

diketene to undergo the oxidative cyclization with alkyne to form the nickelacyclo-

pentene intermediate I (Scheme 6). On the contrary to the mechanism demonstrated

in Scheme 5, the active metallacycle I having PPh3 ligand invokes C–C bond cleavage

reaction via nickel carbene cyclopropane rearrangement to form the nickelacyclo-

pentene IV14. [1,2]-Shift of the Ni atom proceeds to avoid the distortion of the spiro-

β-lactone ring giving rise to the dienylnickelacycle intermediate V, which then

5

OO

R1

R2

NiO

O

Ni

R2

R1

AlEt2X

NiO

R2

R1

OAlEt2X

NiO

R2

R1

O

H+

Et2AlX

R1

R2

AlEt2X

Ni

R1

R2

R1

R2

O

O

AlEt2X

Ni

R1

R2

R1

R2

O

O

AlEt2X

R1

R2

R1

R2

NiXOAlEt2

O

-XH-Ni(0)

R1

R2

R1

R2

CO2H

I II

III

128

undergoes cycloaddition reaction with alkyne to form vinylnickel intermediate VI15.

Intramolecular carbonickelation followed by aromatization (VII, VIII) provides the

alternative regioisomer 6 by transmetalation with Et2Al(OEt) accompanying the libera-

tion of catalytically active Ni(0) species16.

Sterically controlled oxanickelacycle V would afford (3E)-4-ethyl-5-methylene-

3-heptenoic acid 7b with high stereoselectivity by hydrolysis with acid aqueous media.

Instead, the addition of PhMgBr to the reaction mixture would provide (3Z)-4-ethyl-

5-methylene-3-phenyl-3-heptenoic acid 8b via transmetallation with oxanickelacycle

V and (3Z)-4-ethyl-5-methylene-3-[(3Z)-4-phenyl-3-hexenyl]-3-heptenoic acid 9b

from trienylnickel intermediate VI. Although intermediates V and VI could not be

verified by X-ray crystallographic analysis or NMR spectra, highly stereoselective

formations of 7b, 8b, and 9b might prove the formation of nickel intermediates V and

VI in situ. Thus, a mechanism for the formation of 6 involving the stereodefined

nickelacycle V might be conceivable.

129

Scheme 6. Mechanism for the Formation of Phenylacetic Acids via

Ni-Catalyzed Coupling of Diketene, Alkyne, and Organoaluminum in the

Presence of PPh3

R1

R2

Ni OO

Ni

R2

R1

I

LL

L LNi

R2

R1

L L

Ni

R2

R1

L

L

O

OO

O

OO

Ni

R2

R1

IV

OO

LL

R1

ONi

R2

L

LO

R1

R2 Ni+ R1

R2

R2R1 CO2-

R1R2

R2R1

Ni+

CO2-

R1R2

R2 CO2NiHR1

Et2Al(OEt)

-XH-Ni(0)

R1R2

R2 CO2AlEt(OEt)R1

R1R2

R2 CO2HR1

V

VI VII VIII

6

130

In conclusion, the multicomponent coupling reaction of diketene, alkyne, and

Me2Zn has been demonstrated to give 3-methylene-4-hexenoic acids in excellent yields.

Under similar conditions, the combination of Ni catalyst and Et2Al(OEt) accelerates

the dimerization of alkyne followed by a [2+2+2] cycloaddition reaction to furnish

phenylacetic acid derivatives. In the presence of PPh3, a formal [2+2+1+1]

cycloaddition reaction proceeds to afford the alternative regioisomer of phenylacetic

acid derivatives accompanying the C–C double bond cleavage reaction of diketene.

Synthetic applications involving the cleavage reaction of various C–C double bonds

are currently under investigation.

131
















JEOL JMS-DX303.


Tetrahydrofuran was dried and distilled from benzophenone and sodium

immediately prior to use under nitrogen atmosphere. Anhydrous toluene was

purchased (Aldrich) and used without further purification. Ni(acac)2, Ni(cod)2, PPh3,

c-Hex3P, n-Bu3P, Xantphos [4,5-Bis(diphenylphosphino)-9,9-dimethylxanthene],

132

Me2Zn (1.0 M hexane solution), Me3Al (1.0 M hexane solution), Et3Al (1.0 M hexane

solution), Et2AlCl (1.0 M hexane solution), Et2Al(OEt) (1.0 M hexane solution),

PhMgBr (1.0 M THF solution) (Kanto Kagaku) were purchased and used without

further purification. 2-Butyne, 3-hexyne, 4-octyne, 5-decyne, bis(trimethylsilyl)acety-

lene, diphenylacetylene, 1-phenyl-2-(trimethylsilyl)acetylene, 1-trimethylsilyl-1-prop-

yne, 3,3-dimethyl-1-butyne, trimethylsilylacetylene, and 1-phenyl-1-butyne (Tokyo

Kasei Kogyo Co., Ltd) were purchased and distilled prior to use. Diketene (Tokyo

Kasei Kogyo Co., Ltd) was purchased and used without further purification.

133

General procedure 1: Formation of Unsaturated Carboxylic Acids from Diketene

Promoted by Ni Catalyst (entry 2, Table 1)





flask was charged successively via syringe with freshly dry THF (5 mL), diketene

(126.1 mg, 1.5 mmol), and 3-hexyne (82.1 mg, 1 mmol). Dimethylzinc (1.2 mmol, 1.0

M hexane solution) was added slowly at room temperature via the dropping funnel over

a period of 10 min. The mixture was stirred at 50 ℃ for 24 h and monitored by TLC.

After the reaction was completed, the reaction mixture was cooled to 0 ˚C, and then

poured into ice-water. The resulting solution was diluted with 30 mL of EtOAc and

carefully washed with 2 M HCl, with sat. NaHCO3, and brine. The aqueous layer was

extracted with 30 mL of EtOAc. The combined organic phases were dried (MgSO4)

and concentrated in vacuo, and the residual oil was subjected to column

chromatography over silica gel (eluent; hexane/EtOAc = 4/1 v/v) to afford 3b as a

colorless oil (173.2 mg, 95%; Rf = 0.33; hexane/EtOAc = 4/1 v/v).

134

(E)-4-Ethyl-5-methyl-3-methylenehept-4-enoic acid: (3b)

(E)-4-Ethyl-5-methyl-3-methylenehept-4-enoic acid (3b): IR (neat) 2964 (s), 2934

(s), 2874 (s), 2584 (brs), 1711 (s), 1630 (m), 1406 (m), 1375 (m), 907 (s) cm-1; 1H

NMR (400 MHz, CDCl3) δ 0.92 (t, J = 7.6 Hz, 3 H), 0.98 (t, J = 7.6 Hz, 3 H), 1.67 (s,

3 H), 2.06 (q, J = 7.6 Hz, 2 H), 2.10 (q, J = 7.6 Hz, 2 H), 3.10 (s, 2 H), 4.84 (d, J = 1.9

Hz, 1 H), 5.18 (d, J = 1.9 Hz, 1 H); 13C NMR (100 MHz, CDCl3) δ 13.0, 13.4, 19.0,



100), 137 (26).

4,5-Dimethyl-3-methylenehex-4-enoic acid: (3a)


4,5-Dimethyl-3-methylenehex-4-enoic acid (3a): IR (neat) 3085 (br), 2976 (s), 2920

(s), 2862 (s), 2679 (m), 2573 (m), 1713 (s), 1636 (m), 1412 (m), 1294 (s), 907 (s) cm-1;

1H NMR (CDCl3, 400 MHz) δ 1.68 (s, 3 H), 1.70 (s, 3 H), 1.73 (s, 3 H), 3.14 (s, 2 H),

4.78 (d, J = 1.7 Hz, 1 H), 5.12 (d, J = 1.7 Hz, 1 H); 13C NMR (CDCl3, 100 MHz) δ


Et OH

O

Et

Me

Me OH

O

Me

Me

135


100), 140 (68), 139 (100), 137 (24), 125 (32).

(E)-5-Methyl-3-methylene-4-propyloct-4-enoic acid: (3c)


(E)-5-Methyl-3-methylene-4-propyloct-4-enoic acid (3c): IR (neat) 3074 (br), 2931

(s), 2872 (s), 2682 (br), 2598 (br), 1713 (s), 1632 (m), 1410 (m), 1302 (s), 1223 (m),

905 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.87 (t, J = 7.6 Hz, 3 H), 0.89 (t, J = 7.6

Hz, 3 H), 1.32 (sext, J = 7.6 Hz, 2 H), 1.40 (sext, J = 7.6 Hz, 2 H), 1.67 (s, 3 H), 2.03 (t,

J = 7.6 Hz, 2 H), 2.07 (t, J = 7.6 Hz, 2 H), 3.10 (s, 2 H), 4.83 (d, J = 2.0 Hz, 1 H), 5.17

(d, J = 2.0 Hz, 1 H); 13C NMR (CDCl3, 100 MHz) δ 13.9, 14.0, 19.5, 21.4, 21.7, 32.2,

35.6, 41.4, 116.8, 132.0, 134.8, 141.9, 177.3; High-resolution MS, calcd for C13H22O2:

210.1620. Found m/z (relative intensity): 211 (M++1, 2), 210.1612 (M+, 10), 167 (9),

135 (22), 121 (100).

(Z)-3-Methylene-4,5-bis(trimethylsilyl)hex-4-enoic acid: (3d)


n-Pr OH

O

n-Pr

Me

TMS OH

O

TMS

Me

136

(Z)-3-Methylene-4,5-bis(trimethylsilyl)hex-4-enoic acid (3d): IR (neat) 2952 (s),

2900 (s), 2580 (brs), 2343 (s), 1712 (s), 1624 (m), 1406 (m), 1249 (s), 893 (m), 839 (s),

756 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.18 (s, 9 H), 0.19 (s, 9 H), 1.84 (s, 3 H),

2.99 (s, 2 H), 4.58 (d, J = 3.1 Hz, 1 H), 5.09 (d, J = 3.1 Hz, 1 H); 13C NMR (CDCl3,

100 MHz) δ 1.25, 1.85, 22.0, 42.3, 111.4, 145.4, 150.0, 155.6, 175.6; High-resolution


270.1477 (M+, 58), 255 (100), 241 (2).

(Z)-3-methylene-4,5-diphenylhex-4-enoic acid: (3e)


(Z)-3-methylene-4,5-diphenylhex-4-enoic acid (3e): IR (neat) 3020 (br), 2914 (m),

2856 (w), 1709 (s), 1599 (m), 1489 (m), 1443 (s), 1265 (m), 762 (s), 698 (s) cm-1; 1H

NMR (CDCl3, 400 MHz) δ 2.28 (s, 3 H), 3.00 (s, 2H), 5,36 (d, J = 1.7 Hz, 1 H), 5,44

(d, J = 1.7 Hz, 1 H), 6.94-7.19 (m, 10 H); 13C NMR (CDCl3, 100 MHz) δ 23.1, 40.9,

118.9, 126.0, 126.2, 127.5, 127.5, 129.0, 130.2, 136.3, 138.7, 139.5, 141.8, 143.4,

176.8; High-resolution MS, calcd for C19H18O2: 278.1307 Found m/z (relative

intensity): 279 (M++1, 8), 278.1312 (M+, 33.7), 219 (100), 204 (26).

(E)-4-Methyl-3-methylene-5-(trimethylsilyl)hex-4-enoic acid: (3f)


Ph OH

O

Ph

Me

137

(E)-4-Methyl-3-methylene-5-(trimethylsilyl)hex-4-enoic acid (3f): IR (neat) 3091

(br), 2957 (br), 2916 (br), 2862 (m), 1713 (s), 1638 (m), 1603 (s), 1408 (s), 1250 (s),

907 (m), 837 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.15 (s, 9 H), 1.68 (s, 3 H), 1.89

(s, 3 H), 3.14 (s, 2 H), 4.86 (d, J = 1.5 Hz, 1 H), 5.14 (d, J = 1.5 Hz, 1 H); 13C NMR

(CDCl3, 100 MHz) δ 0.26, 19.7, 22.8, 41.3, 115.4, 130.6, 144.2, 145.8, 177.3;

High-resolution MS, calcd for C11H20O2Si: 212.1233. Found m/z (relative intensity):

212.1215 (M+, 14), 198 (16), 197 (100).

(Z)-3-Methylene-5-(trimethylsilyl)-4-phenylhex-4-enoic acid: (3g)


(Z)-3-Methylene-5-(trimethylsilyl)-4-phenylhex-4-enoic acid (3g): (a mixture of

regioisomers in a 3 : 1 ratio): IR (neat) 3061 (br), 2960 (br), 2899 (br), 2862 (br), 2677

(m), 1638 (m), 1711 (s), 1408 (m), 1248 (s), 908 (m), 837 (s), 762 (m), 702 (s), 633

(m) cm-1; 1H NMR (CDCl3, 400 MHz, major isomer) δ -0.21 (s, 9 H), 1.92 (s, 3 H),

2.93 (s, 2 H), 5.12 (d, J = 1.7 Hz, 1 H), 5.26 (d, J = 1.7 Hz, 1 H), 7.12-7.16 (m, 2 H),

7.22-7.26 (m, 2 H), 7.26 (m, 1 H); 13C NMR (CDCl3, 100 MHz, major isomer) δ 0.77,

20.6, 41.2, 117.6, 127.8, 128.5, 129.5, 136.5, 142.0, 149.9, 151.4, 177.0; 1H NMR

(CDCl3, 400 MHz, minor isomer) δ -0.21 (s, 9 H), 2.02 (s, 3 H), 3.15 (s, 2 H), 4.83 (d,

TMS OH

O

Me

Me

TMS OH

O

Ph

Me

138

J = 1.5 Hz, 1 H), 5.21 (d, J = 1.5 Hz, 1 H), 7.12-7.16 (m, 2 H), 7.26-7.31 (m, 2 H),

7.26 (m, 1 H); 13C NMR (CDCl3, 100 MHz, minor isomer) δ 0.77, 24.4, 43.3, 113.9,


C16H22O2Si: 274.1389. Found m/z (relative intensity): 275 (M++1, 9), 274.1377 (M+,

37), 260 (21), 259 (100), 241 (10).

(E)-4-Ethyl-3-methylene-5-phenylhex-4-enoic acid: (3h)


(E)-4-Ethyl-3-methylene-5-phenylhex-4-enoic acid (3h): (a mixture of regioisomers

in a 10 : 1 ratio): IR (neat) 2968 (s), 2931 (s), 2594 (brs), 1708 (s), 1629 (m), 1598 (m),

1490 (m), 1438 (m), 1407 (m), 1296 (s), 910 (s), 765 (s), 702 (s) cm-1; 1H NMR

(CDCl3, 400 MHz, major isomer) δ 0.84 (t, J = 7.3 Hz, 3 H), 1.98 (q, J = 7.3 Hz, 2 H),

1.98 (s, 3 H), 3.21 (s, 2 H), 5.05 (d, J = 1.6 Hz, 1 H), 5.34 (d, J = 1.6 Hz, 1 H), 7.12

(dd, J = 7.4, 1.4 Hz, 2 H), 7.23 (td, J = 7.4, 1.4 Hz, 1 H), 7.32 (t, J = 7.4 Hz, 2 H); 13C

NMR (CDCl3, 100 MHz, major isomer) δ 13.2, 22.5, 24.4, 40.9, 117.9, 126.1, 127.7,

128.0, 129.2, 133.4, 138.4, 140.5, 144.0, 175.7; 1H NMR (CDCl3, 400 MHz, minor

isomer) δ 0.94 (t, J = 7.3 Hz, 3 H), 1.98 (q, J = 7.3 Hz, 2 H), 2.17 (s, 3 H), 2.92 (s, 2 H),

5.15 (d, J = 1.6 Hz, 1 H), 5.27 (d, J = 1.6 Hz, 1 H), 7.10-7.32 (m, 5 H); 13C NMR

(CDCl3, 100 MHz, minor somer) δ 13.0, 18.8, 28.0, 30.9, 117.9, 126.4, 127.7, 127.9,

129.2, 133.4, 138.4, 140.5, 144.0, 175.7; High-resolution MS, calcd for C15H18O2:

Ph OH

O

Et

Me

139


201 (100).

General procedure 2: Formation of Unsaturated Carboxylic Acids from Diketene

with Organoaluminum Promoted by Ni Catalyst (entry 5, Table 2)




with Ni(cod)2 (27.5 mg, 0.1 mmol). The apparatus was purged with nitrogen and the

flask was charged successively via syringe with freshly dry toluene (3 mL), diketene

(252.2 mg, 3.0 mmol), and 3-hexyne (82.1 mg, 1 mmol). Oganoaluminum (1.2 mmol,

1.0 M hexane solution) was added slowly at room temperature via the dropping funnel

over a period of 10 min (the reaction temperature should not be exceeded 50 ˚C). The

mixture was stirred at room temperature for 72 h and monitored by TLC. After the



washed with 2 M HCl, and brine. The aqueous layer was extracted with 30 mL of

EtOAc. The combined organic phases were dried (MgSO4) and concentrated in vacuo,

and the residual oil was subjected to column chromatography over silica gel (eluent;

hexane/EtOAc = 10/1 v/v) to afford 4ba as a colorless oil (63.5 mg, 24%; Rf = 0.40;

hexane/EtOAc = 4/1 v/v).

140

(4Z,6E)-4,5,6-Triethyl-7-methyl-3-methylenenona-4,6-dienoic acid: (4ba)

(4Z,6E)-4,5,6-Triethyl-7-methyl-3-methylenenona-4,6-dienoic acid (4ba) : IR

(neat) 2966 (s), 2933 (s), 2874 (s), 2675 (br), 1711 (s), 1410 (m), 1296 (m), 905 (m)

cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.91 (t, J = 7.3 Hz, 6 H), 0.97 (t, J = 7.3 Hz, 6 H),

1.67 (s, 3 H), 2.05 (q, J = 7.3 Hz, 4 H), 2.10 (q, J = 7.3 Hz, 4 H), 3.10 (s, 2 H), 4.85 (d,

J = 1.9 Hz, 1 H), 5.18 (d, J = 1.9 Hz, 1 H); 13C NMR (CDCl3, 100 MHz) δ 13.0, 13.4,

19.0, 23.1, 26.5, 41.2, 116.9, 130.1, 132.0, 133.0, 135.6, 141.7, 176.4; High-resolution

MS, calcd for C17H28O2: 264.2089. Found m/z (relative intensity): 265 (M++1, 9),

264.2076 (M+, 58), 249 (21), 235 (100), 221 (30).

(Z)-4,5,6,7-Tetraethyl-3-methylenenona-4,6-dienoic acid: (4bb)


(Z)-4,5,6,7-Tetraethyl-3-methylenenona-4,6-dienoic acid (4bb) : IR (neat) 2964 (s),

2873 (s), 2677 (br), 2347 (br), 1709 (s), 1630 (m), 1410 (m), 1296 (m), 905 (m), 864

Et OH

O

Et

EtEt

Me

Et OH

O

Et

EtEt

Et

141

(m) cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.83-1.10 (m, 15 H), 1.99-2.14 (m, 10 H),

3.09 (dd, J = 1.2, 0.7 Hz, 2 H), 4.85 (dt, J = 2.0, 0.7 Hz, 1 H), 5.14 (dt, J = 2.0, 1.2 Hz,

1 H); 13C NMR (CDCl3, 100 MHz) δ 13.2, 13.5, 14.0, 20.0, 22.8, 23.0, 25.3, 41.6,



249 (100), 235 (44).

General procedure 3: Formation of Phenylacetic acids from Diketene with

Promoted by Ni Catalyst (entry 8, Table 2)




charged with Ni(cod)2 (27.5 mg, 0.1 mmol). The apparatus was purged with nitrogen

and the flask was charged successively via syringe with freshly dry toluene (3 mL),

diketene (252.2 mg, 3.0 mmol), and 3-hexyne (82.1 mg, 1 mmol). Oganoaluminum

(1.2 mmol, 1.0 M hexane solution) was added slowly at room temperature via the

dropping funnel over a period of 10 min (the reaction temperature should not be

exceeded 50 ˚C). The mixture was stirred at room temperature for 72 h and

monitored by TLC. After the reaction was completed, the reaction mixture was


with 30 mL of EtOAc and carefully washed with 2 M HCl, and brine. The aqueous

142

layer was extracted with 30 mL of EtOAc. The combined organic phases were dried

(MgSO4) and concentrated in vacuo, and the residual oil was subjected to column

chromatography over silica gel (eluent; hexane/EtOAc = 4/1 v/v) to afford 5b as a

colorless oil (121.8 mg, 98%; Rf = 0.67; hexane/EtOAc = 4/1 v/v).

2-(2,3,4,5-Tetraethylphenyl)acetic acid: (5b)


2-(2,3,4,5-Tetraethylphenyl)acetic acid (5b) : IR (KBr) 3086 (br), 2970 (s), 2933 (s),

2862 (s), 2674 (s), 2675 (m), 1709 (s), 1628 (m), 1377 (m), 1034 (m), 874 (m), 835

(m) cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.12-1.28 (m, 12 H), 2.59-2.70 (m, 8 H), 3.65

(s, 2 H), 6.92 (s, 1 H); 13C NMR (CDCl3, 100 MHz) δ 15.2, 15.39, 15.42, 15.8, 21.8,

22.1, 22.3, 25.5, 38.3, 128.6, 129.1, 138.1, 139.4, 139.7, 140.2, 175.6; High-resolution


248.1770 (M+, 100), 233 (43).

2-(2,3,4,5-Tetramethylphenyl)acetic acid: (5a)


OH

O

EtEt

EtEt

143

2-(2,3,4,5-Tetramethylphenyl)acetic acid (5a) : IR (KBr) 3086 (s), 2931 (s), 2871 (s),

2725 (br), 2534 (m), 1717 (s), 1693 (s), 1628 (m), 1460 (m), 1408 (s), 935 (s), 814 (m),

750 (m), 679 (m) cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.18 (s, 3 H), 2.20 (s, 3 H), 2.21

(s, 3 H), 2.25 (s, 3 H), 3.64 (s, 2H), 6.86 (s, 1 H); 13C NMR (CDCl3, 100 MHz) δ 16.1,

16.2, 16.4, 20.6, 39.3, 128.8, 129.4, 132.6, 133.7, 134.4, 135.5, 175.7; High-resolution


192.1147 (M+, 22), 147 (100), 132 (16).

2-(2,3,4,5-Tetrapropylphenyl)acetic acid: (5c)


2-(2,3,4,5-Tetrapropylphenyl)acetic acid (5c) : IR (KBr) 3086 (br), 2959 (s), 2930

(s), 2872 (s), 2662 (br), 2561 (m), 1713 (s), 1651 (m), 1456 (s), 883 (m), 739 (m), 610

(m) cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.96-1.06 (m, 12 H), 1.39-1.65 (m, 8 H), 2.53

(m, 8 H), 3.61 (s, 2H), 6.88 (s, 1 H); 13C NMR (CDCl3, 100 MHz) δ 14.8, 14.9, 15.0,

24.3, 24.5, 24.6, 24.9, 31.6, 31.9, 32.0, 35.0, 38.6, 129.0, 136.8, 138.1, 138.2, 139.1,

OH

O

MeMe

MeMe

OH

O

n-Prn-Pr

n-Prn-Pr

144

177.0; High-resolution MS, calcd for C20H32O2: 304.2402. Found m/z (relative

intensity): 305 (M++1, 22), 304.2409 (M+, 100), 275 (40), 259 (3).

2-(2,3,4,5-tetrabutylphenyl)acetic acid: (5j)


2-(2,3,4,5-tetrabutylphenyl)acetic acid (5j) : IR (KBr) 2953 (s), 2858 (d), 2667 (brs),

2341 (d), 1712 (s), 1651 (s), 1463 (s), 1409 (s), 1377 (s), 1240 (s), 1103 (s), 1047 (s),

948 (brs), 846 (s), 802 (s), 729 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.96 (m, 12 H),

1.45 (m, 16 H), 2.55 (m, 8 H), 3.61 (s, 2 H), 6.87 (s, 1 H); 13C NMR (CDCl3, 100

MHz) δ 13.8, 14.0, 23.0, 23.4, 23.5, 23.6, 28.9, 29.2, 29.3, 32.6, 33.2, 33.5, 33.7, 33.8,


C24H40O2: 360.3028 Found m/z (relative intensity): 361 (M++1, 26), 360.3014 (M+,

100), 275 (11).

2-{(2,3,4,5-tetrahenyl)phenyl}acetic acid: (5e)


OH

O

n-Bun-Bu

n-Bun-Bu

145

2-{(2,3,4,5-tetrahenyl)phenyl}acetic acid (5e): IR (neat) 3051 (br), 2932 (m), 2874

(m), 2500 (m), 1709 (s), 1601 (m), 1560 (m), 1493 (m), 1443 (m), 1265 (s), 1157 (m),

739 (s), 770 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 3.60 (s, 2 H), 6.74-7.14 (m, 20 H),

7.46 (s, 1H) ; 13C NMR (CDCl3, 100 MHz) δ 39.1, 125.2, 125.4, 126.0, 126.1, 126.4,

126.4, 126.7, 127.4, 127.4, 129.8, 130.2, 131.0, 131.0, 131.3, 139.2, 139.3, 139.6,


440.1776. Found m/z (relative intensity): 441 (M++1, 61), 440.1779 (M+, 66.7), 395

(100).

2-(2,4-dimethyl-5-(trimethylsilyl)phenyl)acetic acid: (5f’)


2-(2,4-dimethyl-5-(trimethylsilyl)phenyl)acetic acid (5f’) : IR (neat) 3415 (br), 2932

(s), 2873 (s), 2578 (brs), 2363 (s), 1712 (s), 1635 (d), 1448 (s), 1409 (s), 1375 (s), 1249

(s), 1209 (s), 1151 (s), 1031 (s), 839 (s), 758 (s), 690 (s) cm-1; 1H NMR (CDCl3, 400

MHz) δ 0.30 (s, 9 H), 2.28 (s, 3 H), 2.40 (s, 3 H), 3.64 (s, 2 H), 6.99 (s, 1 H), 7.23 (s, 1

OH

O

PhPh

PhPh

OH

O

TMSMe

HMe

146

H); 13C NMR (CDCl3, 100 MHz) δ -0.1, 19.3, 22.5, 38.4, 128.4, 131.0, 135.8, 136.4,

137.7, 142.9, 176.5; High-resolution MS, calcd for C13H20O2Si: 236.1233 Found m/z

(relative intensity): 237 (M++1, 10), 236.1218 (M+, 65), 222 (19), 221 (100).

2-(3,5-di-tert-butylphenyl)acetic acid: (5k)


2-(3,5-di-tert-butylphenyl)acetic acid (5k) : IR (neat) 3203 (br), 2964 (s), 2870 (s),

2360 (s), 2341 (s), 1710 (s), 1599 (s), 1409 (s), 1363 (s), 1265 (s), 894 (s), 738 (s)

cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.32 (s, 18 H), 3.64 (s, 2 H), 7.12 (d, J = 1.71 Hz,

2 H), 7.34 (t, J = 1.71 Hz, 1 H); 13C NMR (CDCl3, 100 MHz) δ 31.4, 34.8, 41.3, 121.2,

123.4, 132.2, 150.9, 176.2; High-resolution MS, calcd for C16H24O2: 248.1776 Found


2-(3,5-bis(trimethylsilyl)phenyl)acetic acid: (5l)


OH

O

t-BuH

t-BuH

OH

O

TMSH

TMSH

147

2-(3,5-bis(trimethylsilyl)phenyl)acetic acid (5l) : IR (neat) 2956 (s), 2570 (brs), 1712

(s), 1645 (d), 1408 (s), 1377 (s), 1303 (s), 1249 (s), 1209 (s), 1151 (s), 1032 (s), 860 (s),

837 (s), 756 (s), 694 (s) cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.27 (s, 18 H), 3.65 (s, 2

H), 7.41 (d, J = 0.97 Hz, 2 H), 7.57 (d, J = 0.97 Hz, 1 H); 13C NMR (CDCl3, 100 MHz)

δ -1.1, 41.1, 113.9, 134.7, 137.4, 139.9, 176.6; High-resolution MS, calcd for

C14H24O2Si2: 280.1315 Found m/z (relative intensity): 281 (M++1, 8), 280.1313 (M+,

33), 265 (100), 237 (55).

2-(5,8-diethyl-1,2,3,4-tetrahydronaphthalen-6-yl)acetic acid: (5i)


2-(5,8-diethyl-1,2,3,4-tetrahydronaphthalen-6-yl)acetic acid (5i) : IR (KBr)

3312-2542 (br), 1692 (s), 1454 (s), 1420 (s), 1227 (s), 939 (m), 912 (m), 877 (m) cm-1;

1H NMR (CDCl3, 400 MHz) δ 1.03 (t, J = 7.56 Hz, 3 H), 1.19 (t, J = 7.56 Hz, 3 H),

1.77-1.78 (m, 4 H), 2.54 (q, J = 7.56 Hz, 2 H), 2.62 (q, J = 7.56 Hz, 2 H), 2.68 (t, J =

6.10 Hz, 2 H) , 2.75 (t, J = 6.10 Hz, 2 H) 3.65 (s, 2 H), 7.24 (s, 1 H); 13C NMR (CDCl3,

100 MHz) δ 13.9, 14.1, 21.8, 22.7, 23.1, 25.4, 26.6, 26.9, 38.4, 127.5, 128.3, 134.7,

135.4, 138.2, 139.7, 177.8; High-resolution MS, calcd for C16H22O2 : 246.1620. Found

m/z (relative intensity): 247 (M++1, 36), 246.1538 (M+, 100), 231 (41), 217 (75), 201

Et

EtOH

O

148

(36).

2-(2,3,5,6-Tetramethylphenyl)acetic acid: (6a)


2-(2,3,5,6-Tetramethylphenyl)acetic acid (6a) : IR (KBr) 3086 (br), 3002 (s), 2924

(s), 2874 (s), 2732 (br), 2332 (m), 1695 (s), 1607 (m), 1408 (m), 1381 (m), 1213 (s),

1010 (m), 935 (m), 868 (m), 681 (m) cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.20 (s, 6 H),

2.23 (s, 3 H), 2.24 (s, 3 H), 3.79 (s, 2 H), 6.91 (s, 1 H); 13C NMR (CDCl3, 100 MHz) δ



76), 147 (100).

2-(2,3,5,6-Tetraethylphenyl)acetic acid: (6b)


2-(2,3,5,6-Tetraethylphenyl)acetic acid (6b) : IR (KBr) 3103 (br), 2968 (s), 2936 (s),

OH

O

MeMe

MeMe

OH

O

EtEt

EtEt

149

2876 (s), 2719 (br), 2363 (m), 1699 (s), 1483 (m), 1416 (s), 1231 (s), 939 (m), 887 (s),

802 (m), 656 (m) cm-1; 1H NMR (CDCl3, 400 MHz) δ 1.12 (t, J = 7.6 Hz, 6 H), 1.23 (t,

J = 7.6 Hz, 6 H), 2.63 (q, J = 7.6 Hz, 4 H), 2.64 (q, J = 7.6 Hz, 4 H), 3.79 (s, 2 H), 6.98

(s, 1 H); 13C NMR (CDCl3, 100 MHz) δ 14.8, 15.5, 22.3, 25.7, 34.4, 128.1, 129.4,

138.2, 139.3, 177.8; High-resolution MS, calcd for C16H24O2: 248.1776. Found m/z

(relative intensity): 249 (M++1, 14), 248.1770 (M+, 77), 233 (16), 203 (17), 189 (100).

2-(2,3,5,6-Tetrapropylphenyl)acetic acid: (6c)


2-(2,3,5,6-Tetrapropylphenyl)acetic acid (6c) : IR (KBr) 3103 (br), 2957 (s), 2932

(s), 2870 (s), 2711 (br), 2354 (m), 1703 (s), 1562 (m), 1454 (s), 1414 (m), 1018 (m),

912 (m), 791 (m) cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.99 (t, J = 7.6 Hz, 6 H), 1.01 (t,

J = 7.6 Hz, 6 H), 1.45 (sext, J = 7.6 Hz, 4 H), 1.59 (sext, J = 7.6 Hz, 4 H), 2.50 (t, J =

7.6 Hz, 4 H), 2.54 (t, J = 7.6 Hz, 4 H), 3.75 (s, 2H), 6.91 (s, 1 H); 13C NMR (CDCl3,

100 MHz) δ 14.4, 14.8, 24.0, 24.5, 31.9, 34.8, 35.2, 129.7, 130.0, 137.3, 138.0, 177.7;

High-resolution MS, calcd for C20H32O2: 304.2402. Found m/z (relative intensity):

304.2392 (M+, 100), 275 (56), 245 (57).

OH

O

n-Prn-Pr

n-Prn-Pr

150

2-(2,3,5,6-tetrabutylphenyl)acetic acid: (6j)


2-(2,3,5,6-tetrabutylphenyl)acetic acid (6j) : IR (neat) 3075 (br), 2957(s), 2930 (s),

2860 (s), 2669 (m), 2343 (m), 1709 (s), 1464 (m), 1410 (m), 1379 (m), 1292 (m), 1227

(m), 930 (m), 899 (m) cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.95 (m, 12 H), 1.38-1.46

(m, 16 H), 2.52-2.58 (m, 8 H), 3.75 (s, 1 H), 6.91. (s, 2 H) ; 13C NMR (CDCl3, 100

MHz) δ 13.8, 13.9, 14.0, 23.0, 23.4, 29.4, 32.8, 32.9, 33.8, 34.9, 124.6, 129.7, 129.9,

137.3, 138.2, 140.1, 178.6 ; High-resolution MS, calcd for C24H40O2: 360.3028. Found

m/z (relative intensity): 361 (M++1, 26), 360.3055 (M+, 100), 316 (9).

2-{(2,3,5,6-tetrahenyl)phenyl}acetic acid: (6e)


2-{(2,3,5,6-tetrahenyl)phenyl}acetic acid (6e) : IR (neat) 3024 (br), 2866 (s), 2835 (s),

2500 (m), 1717 (s), 1653 (s), 1578 (m), 1420 (s), 1232 (s), 918 (m), 692 (s) cm-1; 1H

NMR (CDCl3, 400 MHz) δ 3.66 (s, 2 H), 7.34-7.69 (m, 21 H); 13C NMR (CDCl3, 100

OH

O

n-Bun-Bu

n-Bun-Bu

OH

O

PhPh

PhPh

151

MHz) δ37.0, 127.4, 127.5, 128.3, 128.4, 128.5, 128.7, 131.9, 132.0, 171.1;

High-resolution MS, calcd for C32H24O2: 440.1776. Found m/z (relative intensity): 441

(M++1, 29), 440.1769 (M+, 43.8), 395 (100).

2-(2,5-dimethyl-3,6-bis(trimethylsilyl)phenyl)acetic acid: (6f)


2-(2,5-dimethyl-3,6-bis(trimethylsilyl)phenyl)acetic acid (6f) : IR(neat) 2959 (s),

2903 (s), 2667 (w), 1705 (s), 1636 (m), 1410 (m), 1252 (s), 1211 (m), 1150 (m), 1032

(m), 837 (s), 760 (s), 691 (m), 635 (m) cm-1; 1H NMR (CDCl3, 400 MHz) δ 0.31 (s, 9 H),

0.41 (s, 9 H), 2.32 (s, 3 H), 2.45 (s, 3 H), 3.93 (s, 2 H), 7.19 (s, 1 H); 13C NMR (CDCl3,

100 MHz) δ 0.0, 0.8, 14.0, 20.1, 38.8, 136.2, 137.2, 139.3, 139.6, 140.0, 140.5, 176.4;

High-resolution MS, calcd for C16H28O2Si2: 308.1628. Found m/z (relative intensity):

308.1634 (M+, 11.1), 293 (100).

2-(2,5-di-tert-butylphenyl)acetic acid: (6k)


OH

O

MeTMS

TMSMe

152

2-(2,5-di-tert-butylphenyl)acetic acid (6k) : IR(neat) 2868 (s), 2550 (s), 2341 (m),

1699 (s), 1464 (s), 1416 (s), 1362 (s), 1231 (s), 1204 (s), 910 (s), 824 (s), 741 (s) cm-1;

1H NMR (CDCl3, 400 MHz) δ 1.29 (s, 9 H), 1.39 (s, 9 H), 3.95 (s, 2 H), 7.21 (s, 1 H),

7. 33 (d, J = 8.5 Hz, 1 H), 7.38 (d, J = 8.5 Hz, 1 H); 13C NMR (CDCl3, 100 MHz) δ

31.2, 31.6, 34.0, 36.5, 40.2, 124.0, 126.0, 130.0, 130.8, 148.4, 149.6, 177.8;

High-resolution MS, calcd for C16H24O2: 248.1776. Found m/z (relative intensity):

248.1768 (M+, 49.5), 233 (100), 216 (2.5), 203 (1.6).

2-(2,5-bis(trimethylsilyl)phenyl)acetic acid: (6l)


2-(2,5-bis(trimethylsilyl)phenyl)acetic acid (6l) : IR(neat) 2955 (s), 2899 (s), 2856

(m), 1713 (s), 1410 (m), 1373 (m), 1250 (s), 839 (s), 752 (s), 691 (m),637 (m) cm-1; 1H

NMR (CDCl3, 400 MHz) δ 0.26 (s, 9 H), 0.33 (s, 9 H), 3.81 (s, 2 H), 7.40 (d, J = 1.0 Hz,

1 H), 7.42 (dd, J = 7.8, 1.0 Hz, 1 H), 7.51 (d, J = 7.3 Hz, 1 H); 13C NMR (CDCl3, 100

MHz) δ -0.9, 0.6, 41.5, 131.8, 134.3, 135.5, 138.0, 140.0, 142.0, 177.8; High-resolution

OH

O

Ht-Bu

t-BuH

OH

O

HTMS

TMSH

153


280.1320 (M+, 0.6), 265 (100).

General procedure for the C–C bond cleavage reaction of diketene promoted by

stoichiometric amount of Ni(0) (Scheme 4)

To a solution of Ni(cod)2 (137.5 mg, 0.5 mmol), and PPh3 (262.3 mg, 1.0 mmol)

in dry toluene (5 mL) were successively added diketene (42.0 mg, 0.5 mmol),

3-hexyne (41.1 mg, 0.5 mmol) via syringe under nitrogen atmosphere. The mixture

was stirred at room temperature for 1 h. After the reaction, added 2 N HCl and stirred

for overnight at room temperature. The mixture was diluted with 30 mL of EtOAc

and washed with brine. The extract was dried (MgSO4) and concentrated in vacuo

and the residual oil was subjected to column chromatography over silica gel

(hexane/EtOAc = 4/1 v/v) to give 7b (67.3 mg, 80%, Rf = 0.33; hexane/EtOAc = 4/1

v/v).

(3E)-4-ethyl-5-methylene-3-heptenoic acid: (7b)

(3E)-4-ethyl-5-methylene-3-heptenoic acid (7b) : IR(neat) 2970 (s), 2936 (s), 2878 (s),

1713 (s), 1607 (m), 1413 (s), 1288 (s), 1219 (s), 893 (s) cm-1; 1H NMR (CDCl3, 400

MHz) δ 0.98 (t, J = 7.5 Hz, 3 H), 1.05 (t, J = 7.5 Hz, 3 H), 2.25 (qd, J = 7.5, 1.3 Hz, 2

H), 2.25 (q, J = 7.5 Hz, 2 H), 3.21 (d, J = 7.1 Hz, 2 H), 4.92 (d, J = 1.3 Hz, 1 H), 5.03

Et OH

OH

Et

154

(s, 1 H), 5.64 (t, J = 7.1 Hz, 1H); 13C NMR (CDCl3, 100 MHz) δ 13.2, 13.4, 21.5, 26.9,


168.1150. Found m/z (relative intensity): 169 (M++1, 83.7), 168.1143 (M+, 51.1), 153

(100).

General procedure for the C–C bond cleavage reaction of diketene promoted by

stoichiometric amount of Ni(0) with PhMgBr (eq 2)

To a solution of Ni(cod)2 (137.5 mg, 0.5 mmol), and PPh3 (262.3 mg, 1.0 mmol)

in dry toluene (5 mL) were successively added diketene (42.0 mg, 0.5 mmol),

3-hexyne (41.1 mg, 0.5 mmol) via syringe under nitrogen atmosphere. The mixture

was stirred at room temperature for 1 h. Then, added the PhMgBr (0.6 mmol, 1M

THF solution) and stirred for overnight at room temperature. After the reaction, added

2 N HCl and stirred for 24 h at room temperature. The mixture was diluted with 30

mL of EtOAc and washed with brine. The extract was dried (MgSO4) and

concentrated in vacuo and the residual oil was subjected to column chromatography

over silica gel (hexane/EtOAc = 4/1 v/v) to give the mixture of 8b and 9b (8b: 63.5 mg,

26%, 9b: 127.2 mg, 39%, Rf = 0.33; hexane/EtOAc = 4/1 v/v).

Et OH

OPh

EtEt OH

O

Et

EtPhEt

8b 9b

155

A mixture of (3Z)-4-ethyl-5-methylene-3-phenyl-3-heptenoic acid (8b) and

(3Z)-4-ethyl-5-methylene-3-[(3Z)-4-phenyl-3-hexenyl]-3-heptenoic acid (9b) in a 1 : 2

ratio : IR(neat) 3402 (br), 3084 (s), 3028 (s), 2966 (s), 2934 (s), 1705 (s), 1636 (s),

1441 (m), 1410 (m), 1286 (m), 943 (s), 897 (s), 766 (s), 700 (s) cm-1; 1H NMR (CDCl3,

400 MHz, (8)) δ 0.90 (t, J = 7.5 Hz, 3 H), 1.05 (t, J = 7.5 Hz, 3 H), 2.31 (q, J = 7.5 Hz,

2 H), 2.33 (q, J = 7.5 Hz, 2 H), 2.78 (s, 2 H), 4.89 (s, 1 H), 5.01 (s, 1 H), 7.08-7.32 (m,

5 H); 13C NMR (CDCl3, 100 MHz, (8b)) δ 11.9, 12.5, 26.0, 28.5, 41.7, 118.4, 126.0,

127.6, 128.9, 139.1, 141.8, 143.0, 145.7, 176.2; High-resolution MS (8b), calcd for

C16H20O2: 244.1463. Found m/z (relative intensity): 245 (M++1, 19.0), 244.1458 (M+,

100), 242 (2.9).

1H NMR (CDCl3, 400 MHz, (9b)) δ 0.86 (t, J = 7.5 Hz, 3 H), 0.87 (t, J = 7.5 Hz, 3 H),

1.02 (t, J = 7.5 Hz, 3 H), 1.06 (t, J = 7.5 Hz, 3 H), 1.85 (q, J = 7.5 Hz, 2 H), 2.31 (q, J

= 7.5 Hz, 2 H), 2.33 (q, J = 7.5 Hz, 2 H), 2.40 (q, J = 7.5 Hz, 2 H), 3.47 (s, 2 H), 4.65

(d, J = 1.5 Hz, 1 H), 4.80 (d, J = 1.5 Hz, 1 H), 7.08-7.32 (m, 5 H); 13C NMR (CDCl3,

100 MHz, (9)) δ 11.9, 12.5, 13.1, 13.2, 25.3, 25.9, 27.4, 28.4, 39.5, 113.2, 126.1, 126.3,

127.0, 127.5, 127.9, 128.7, 138.4, 142.9, 150.2, 176.2; High-resolution MS (9b), calcd

for C22H30O2: 326.2246. Found m/z (relative intensity): 327 (M++1, 42.6), 326.2242

(M+, 72.7), 297 (100), 282 (60.3).

156

X-ray Crystal Structure Determinations. X-ray quality single crystals were grown

from solvent combinations of ethyl acetate/hexane for both of 5b and 6b. All

measurements were made on a Rigaku Saturn724 diffractometer using multi-layer

mirror monochromated Mo-Ka radiation. Data were collected and processed using

CrystalClear (Rigaku) at a temperature of -179+1 ˚C to a maximum 2θ value of 55˚.

The structures were solved by direct methods (SHELXL-97) and expanded using

Fourier techniques. The non-hydrogen atoms were refined anisotropically and

hydrogen atoms were refined using the riding model. All calculations were performed

using the CrystalStructure 4.0 (Crystal Structure Analysis Package, Rigaku

Corporation) except for refinement, which was performed using SHELXL-97. Crystal

data and refinement parameters for the structurally characterized compounds 5b and 6b

are summarized in Tables 4 and 5, respectively. An ORTEP drawing of 5b and 6b are

shown in Figure 1 and 2, respectively. CCDC 832667 contains the supplementary

crystallographic data for 5b and CCDC 828924 for 6b. These data can be obtained

free of charge from the Cambridge Crystallographic Data Centre via

www.ccdc.cam.ac.uk/data_request/cif.

157

Table 4. Crystallographic data for compound 5b Formula C16H24O2

formula weight 248.36

cryst system monoclinic

space group P21/c

cryst color colorless, prism

cryst size (mm) 0.280 x 0.220 x 0.056

a (Å) 16.802(5)

b (Å) 8.257(2)

c (Å) 10.389(3)

α (deg)

β (deg) 97.407(4)

γ (deg)

V (Å3) 1429.4(7)

Z 4

ρcalc (gcm-3) 1.154

µ (cm-1) 0.738

2θmax (deg) 55.0

no. of unique reflns 3255

Rint 0.0466

no. of parameters 168

R1 a[I>2σ(I)] 0.0557

R b(all data) 0.0766

Rw c 0.1186

GOF d 1.091

a R1 = Σ ||Fo| − |Fc||/Σ |Fo|. b

R = Σ |Fo2 − Fc2|/Σ Fo2. c

Rw = {Σw(Fo2 − Fc2)2/Σw

(Fo2)2}1/2. d GOF = [{Σw(Fo2

− Fc2)2}/(No − Np)]1/2, where No and Np denote the number of

observations and parameters.

158

Table 5. Crystal data and data refinement for 6b Formula C16H24O2

formula weight 248.36

cryst system triclinic

space group P-1

cryst color colorless, platelet

cryst size (mm) 0.155 x 0.083 x 0.027

a (Å) 4.876(3)

b (Å) 9.006(6)

c (Å) 16.659(10)

α (deg) 97.07(2)

β (deg) 94.054(8)

γ (deg) 94.82(2)

V (Å3) 721.0(8)

Z 2

ρcalc (gcm-3) 1.144

µ (cm-1) 0.731

2θmax (deg) 54.9

no. of unique reflns 3284

Rint 0.0407

no. of parameters 171

R1 a[I>2σ(I)] 0.0494

R b(all data) 0.0816

Rw c 0.1160

GOF d 1.087

a R1 = Σ ||Fo| − |Fc||/Σ |Fo|. b

R = Σ |Fo2 − Fc2|/Σ Fo2. c

Rw = {Σw(Fo2 − Fc2)2/Σw

(Fo2)2}1/2. d GOF = [{Σw(Fo2

− Fc2)2}/(No − Np)]1/2, where No and Np denote the number of

observations and parameters.

159

References

(1) (a) A. Wahhab, J. Leba, Tetrahedron Lett. 2000, 41, 1487-1490.

(b) D. A. Ketcha, L. J. Wilson, D. E. Portlock, Tetrahedron Lett. 2000, 41,

6253-6257.

(c) C. Spanka, B. Clapham, K. D. Janda, J. Org. Chem. 2002, 67, 3045-3050.

(2) (a) S. O. Lawesson, S. Gronwall, R. Sandberg, Org. Syn. 1962, 42, 28-29.

(b) A. Nudelman, R. Kelner, N. Broida, H. E. S. Gottlieb, Synthesis 1989,

387-388.

(3) (a) K. Itoh, M. Fukui, Y. Kurachi, J. Chem. Soc. Chem. Commun. 1977, 500-501.

(b) K. Itoh, T. Yogo, Y. Ishii, Chem. Lett. 1977, 103-106.

(c) K. Itoh, T. Harada, H. Nagashima. Bull. Chem. Soc. Jpn. 1991, 64,

3746-3748.

(d) P. S. Aroa, Q. N. Van, M. Famulok, A. J. Shaka, J. S. Nowick, Bio&Med.

Chem. 1998, 6, 1421-1428.

(4) (a) Y. Tezuka, T. Ogura, S. Kawaguchi, Bull. Chem. Soc. Jpn. 1969, 42,

443-446.

(b) T. Yamamoto, J. Ishizu, A. Yamamoto, Bull. Chem. Soc. Jpn. 1982, 55,

623-624.

160

(c) T. Fujisawa, T. Sato, Y. Gotoh, M. Kawashima, T. Kawara, Bull. Chem. Soc.

Jpn. 1982, 55, 3555-3559.

(d) Y. Abe, M. Sato, H. Goto, R. Sugawara, E. Takahashi, T. Kato, Chem. Phar.

Bull. 1983, 31, 4346-4354.

(e) A. Duchêne, M. Abarbri, J.-LParrain, M. Kitamura, R. Noyori, Synlett 1994,

524-526.

(f) M. Abarbri, J.-L. Parrain, M. Kitamura, R. Noyori, A. Duchêne, J. Org. Chem.

2000, 65, 7475-7478.

(5) (a) K. M. Engle, D.-H. Wang, J.-Q. Yu, J. Am. Chem. Soc. 2010, 132,

14137-14151.

(b) D.-H. Wang, K. M. Engle, B.-F. Shi, J.-Q. Yu, Science, 2010, 327, 315-319.

(6) (a) T. Leon, A. Correa, R. Martin, J. Am. Chem. Soc. 2013, 135, 1221-1224.

(b) X.-F. Cheng, Y. Li, Y.-M. Su, F. Yin, J.-Y. Wang, J. Sheng, H. U. Vora, X.-S.

Wang, J.-Q. Yu, J. Am. Chem. Soc. 2013, 135, 1236-1239.

(7) Reviews: (a) J. Montgomery, Acc. Chem. Res. 2000, 33, 467-473.

Reviews: (b) S.-I. Ikeda, Acc. Chem. Res. 2000, 35, 511-519.

Reviews: (c) S. Saito, Y. Yamamoto, Chem. Rev. 2000, 100, 2901-2916.

Reviews: (d) I. Nakamura, Y. Yamamoto, Chem. Rev. 2004, 104, 2127-2198.

(e) J. Montgomery, Angew. Chem. Int. Ed. 2004, 43, 3890-3908; Angew. Chem.

161

2004, 116, 3980-3998.

(f) Y. Tamaru, Modern Organonickel Chemistry; Wiley-VCH: Weinheim, 2005.

(g) R. M. Moslin, K. M. Moslin, T. F. Jamison, Chem. Commun. 2007,

4441-4449.

(h) F.-S. Han, Chem. Soc. Rev. 2013, 42, 5270-5298.

(8) (a) M. Kimura, A. Ezoe, M. Mori, Y. Tamaru, J. Am. Chem. Soc. 2005, 127,

201-209.

(b) K. Kojima, M. Kimura, Y. Tamaru, Chem. Commun. 2005, 4717-4719.

(c) M. Kimura, K. Kojima, Y. Tatsuyama, Y. Tamaru, J. Am. Chem. Soc. 2006,

128, 6332-6333.

(d) M. Kimura, M. Mori, R. Mukai, K. Kojima, Y. Tamaru, Chem. Commun.

2006, 2813-2815.

(e) K. Kojima, M. Kimura, S. Ueda, Y. Tamaru, Tetrahedron 2006, 62,

7512-7520.

(f) M. Kimura, Y. Tatsuyama, K. Kojima, Y. Tamaru, Y. Org. Lett. 2007, 9,

1871-1873.

(g) M. Kimura, M. Togawa, Y. Tatsuyama, K. Matsufuji, Tetrahedron Lett. 2009,

50, 3982-3984.

(h) T. Mori, T. Nakamura, M. Kimura, Org. Lett. 2011, 13, 2266-2269.

162

(9) Ni-Catalyzed [2+2] cycloaddition reaction of alkyne with activated alkenes:

(a) P. Binger A. Brinkman and P. Wedemann, Chem. Ber. 1983, 116, 2920-2930.

(b) D.-J. Haung, D. K. Rayabarapu, L.P. Li. T. Sambaiash and C.-H. Cheng,

Chem. Eur. J. 2000, 6, 3706-3713.

(c) A. Nishimura, M. Ohashi, S. Ogoshi, J. Am. Chem. Soc. 2012, 124,

15692-15695.

(d) A. Nishimura, M. Ohashi, S. Ogoshi, Chem. Lett. 2013, 42, 904-905.

(10) CCDC 832667 contains the supplementary crystallographic data for 5b and

CCDC 828924 for 6b.

These data can be obtained free of charge from the Cambridge Crystallographic

Data Centre via, www.ccdc.cam.ac.uk/data_request/cif.

(11) (a) P. Chini, A. Santambrogio, N. Palladino, J. Chem. Soc. (C) 1967, 830-835.

(b) M. V. Russo, A. Furlani, Tetrahedron Lett. 1976, 30, 2655-2656.

(c) P. Mauret, P. Alphonse, J. Organomet. Chem. 1984, 276, 249-256.

(d) C. Ester, A. Maderna, H. Prizkow, W. Siebelt, Eur. J. Inorg. Chem. 2000,

1177-1184.

(e) C. Müller, R. J. Lachicotte, W. D. Jones, Organometallics 2002, 21,

1975-1981.

163

(12) Intramolecular carbonickelations of alkenylnickel species on sp2 framework via

6-endo-trig cyclization have been reported:

(a) S. Ikeda, H. Miyashita, M. Taniguchi, H. Kondo, M. Okano, Y. Sato, K.

Odashima, J. Am. Chem. Soc. 2002, 124, 12060-12061.

(b) S. Ikeda, R. Sanuki, H. Miyachi, H. Miyashita, M. Taniguchi, K. Odashima, J.

Am. Chem. Soc. 2004, 126, 10331-10338.

(13) Y. Nakao, K. S. Kanyiva, T. Hiyama, J. Am. Chem. Soc. 2008, 130, 2448-2449.

(14) Palladacyclopentene rearrangements involving Pd carbene complex have been

reported by B. M. Trost et al :

(a) B. M. Trost, G. J. Tanoury, J. Am. Chem. Soc. 1988, 110, 1636-1638.

(b) B. M. Trost, M. Yanai, K. Hoogsteen, J. Am. Chem. Soc. 1993, 115,

5294-5295.

(c) B. M. Trost, A. S. K. Hashmi, J. Am. Chem. Soc. 1994, 116, 2183-2184.

(15) Ni-catalyzed β-carbon elimination, see:

(a) P. Binger, A. Brinkumann, P. Wedemann, Chem. Ber. 1983, 116, 2920-2930.

(b) Y. Ni, J. Montgomery, J. Am. Chem. Soc. 2006, 128, 2609-2614.

(c) S. Ikeda, H. Obara, E. Tsuchida, N. Shirai, K. Odashima, Organometallics

2008, 27, 1645-1648.

(d) P. Kumar, J. Louie, Org. Lett. 2012, 14, 2026-2029.

164

(e) Y. Li, Z. Lin, Organometallics 2013, 32, 3003-3011.

(16) Et2Al(OEt) promotes transmetalation with Pd-carboxylate to generate

catalytically active Pd(0) species: J. Takaya, K. Sasano, N. Iwasawa, Org. Lett.

2011, 13, 1698-1701.

165

Publication List

Chapter 1

“Stereoselective Coupling Reaction of Dimethylzinc and Alkyne toward

Nickelacycles”

Takamichi Mori, Toshiyuki Nakamura, Masanari Kimura,

Org. Lett., 13(9), pp. 2266-2269 (2011).

Highlighted in Synfacts, 7, pp.0767-0767 (2011).

“Regio- and Stereoselective Multicomponent Coupling Reaction of Alkynes and

Dimethylzinc Involving Allylnickelacycles”

Takamichi Mori, Toshiyuki Nakamura, Gen Onodera, Masanari Kimura,

Synthesis, 44(15), pp. 2333-2339 (2012).

Chapter 2

“Ni-Catalyzed Homoallylation of Polyhydroxy N,O-Acetals with Conjugated Dienes

Promoted by Triethylborane”

Takamichi Mori, Yusuke Akioka, Gen Onodera, Masanari Kimura,

Molecules, 17(9), pp. 9288-9306 (2014).

166

Chapter 3

“Efficient and Selective Formation of Unsaturated Carboxylic Acids and Phenylacetic

Acids from Diketene”

Takamichi Mori, Yusuke Akioka, Hisaho Kawahara, Ryo Ninokata, Gen Onodera,

Masanari Kimura,

Angew. Chem. Int. Ed., 53(39), pp.10434-10438 (2014).

Other related publications

“Decarboxylative C–C Bond Cleavage Reactions via Oxapalladacycles”

Masanari Kimura, Tomohiko Kohno, Kei Toyoda, Takamichi Mori,

Heterocycles, 82(1), pp. 281-287 (2010).

“Ni-Catalyzed Multi-Component Coupling Reaction of Norbornene, Dimethylzinc,

Butadiene, and Aldimine”

Toshiyuki Nakamura, Takamichi Mori, Mariko Togawa, Masanari Kimura,

Heterocycles, 84(1), pp. 339-347 (2012).

“C–C Bond Formation via 1,2-Addition of a tert-Butylzinc Reagent and Carbonyls

Across Conjugated Dienes”

Yuki Ohira, Maya Hayashi, Takamichi Mori, Gen Onodera, Masanari Kimura,

New J. Chem., 38(1), pp. 330-337 (2014).

167

“Ni-Catalyzed Multicomponent Coupling Reaction of Alkyne, 1,3-Butadiene, and

Me2Zn under Carbon Dioxade”

Yasuyuki Mori, Takamichi Mori, Gen Onodera, Masanari Kimura,

Synthesis, 46(17), pp. 2287-2292 (2014).

“Three-Component Coupling Reaction of Enynes, Carbonyls, and Organozinc

Reagents”

Yuki Ohira, Takamichi Mori, Maya Hayashi, Gen Onodera, Masanari Kimura,

Heterocycles, accepted for publication (ASAP).

DOI: 10.3987/COM-14-S(K)65

naosite: nagasaki university's academic output siteefficient and selective formation of...

Documents